Threes Company: Two or More Unrelated Receptors Pair with the Same Ligand
Izhar Ben-Shlomo and
Aaron J. W. Hsueh
Division of Reproductive Biology, Department of Obstetrics and Gynecology, Stanford University, Stanford, California 94305-5317
Address all correspondence and requests for reprints to: Aaron J. W. Hsueh, Stanford University School of Medicine, Department of Obstetrics and Gynecology, Division of Reproductive Biology, 300 Pasteur Drive, Room A-344, Stanford, California 94305-5317. E-mail: aaron.hsueh{at}stanford.edu.
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ABSTRACT
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Intercellular communication relies on signal transduction mediated by extracellular ligands and their receptors. Although the ligand-receptor interaction is usually a two-player event, there are selective examples of one polypeptide ligand interacting with more than one phylogenetically unrelated receptor. Likewise, a few receptors interact with more than one polypeptide ligand, and sometimes with more than one coreceptor, likely through an interlocking of unique protein domains. Phylogenetic analyses suggest that for certain triumvirates, the matching events could have taken place at different evolutionary times. In contrast to a few polypeptide ligands interacting with more than one receptor, we found that many small nonpeptide ligands have been paired with two or more plasma membrane receptors, nuclear receptors, or channels. The observation that many small ligands are paired with more than one receptor type highlights the utilitarian use of a limited number of cellular components during metazoan evolution. These conserved ligands are ubiquitous cell metabolites likely favored by natural selection to establish novel regulatory networks. They likely possess structural features useful for designing agonistic and antagonistic drugs to target diverse receptors.
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INTRODUCTION
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IT IS BELIEVED THAT eukaryotic unicellular organisms evolved more than 2 billion years after the appearance of prokaryotes. Yet, present day multicellular organisms, in all their stunning complexity, evolved within the next 600800 million years. During the evolution of these complex organisms that was associated with only a limited expansion of the total gene pool, two parallel and interacting mechanisms are evident. The first is the widely studied change in protein structure through gene mutations, duplication, and conversion. The second, less obvious, mechanism is the emergence of novel interactions between preexisting cellular components. The recent availability of completely sequenced genomes of model organisms enables the tracing of orthologs and thereby allows a glimpse into the implied novel interactions that occurred during evolution.
Multicellularity requires coordination and a division of labor among different cell groups. Although some unicellular eukaryotes use intercellular signaling for mating (e.g. yeast) or for transition into quasi-multicellular reproductive forms (e.g. slime mold), intercellular signaling exists mainly in multicellular organisms. Cells secrete metabolites, excess nutrients, and protein by- products, some of which have the potential to interact with other cells to serve as signaling molecules.
The emergence of intercellular signal transduction networks can be traced by comparative genomic analyses of ligands and their receptors. The initial pairing of ligand and receptor was likely a random event, although, once coupled, natural selection maintained and even augmented the union by increasing the affinity between the partners. Although the ligand-receptor interaction is usually a two-player event, one can find triumvirates in which ligands interact with two phylogenetically unrelated receptors, thereby activating disparate signaling pathways. Likewise, a few receptors interact with two or more unrelated ligands. Phylogenetic tracing has provided evidence that in ancient times ligands paired with one receptor, and later some paired with a second, thus increasing the complexity of signal transduction in cellular communication.
Herein we review a multitude of examples regarding ligands that activate more than one type of receptor (Table 1
) and receptors that have more than one type of ligand. These findings suggest that, during evolution, a small set of ligands interacted with diverse human plasma membrane receptors and ion channels/transporters, thus allowing focused searches for potential pharmaceutical agents as agonists or antagonists in the future.
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POLYPEPTIDE LIGANDS ACTIVATE MORE THAN ONE UNRELATED RECEPTOR
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Although most polypeptide ligands interact with one receptor or, in some cases, several paralogous receptors with similar evolutionary origins (1), one can find examples of polypeptide ligands interacting with two or more phylogenetically unrelated receptors. To reveal the sequence of ligand-receptor pairing during evolution, we have traced the emergence of each ligand and receptor genes (Table 1
).
Netrin Binds to Three Unrelated Receptors
Netrin ligands guide neuronal growth and, activating two receptor types, the same ligand attracts some neuronal cells but repels others (2, 3). The attraction receptor in human is known as DCC (deleted in colorectal carcinoma), which has highly conserved orthologs in Caenorhabditis elegans [uncoordinated (UNC)-40], Drosophila melanogaster (frazzled), zebrafish (4), and rodents (5). The repulsion receptor for netrin is restricted cardiomyopathy (RCM) in mammals and UNC-5 in C. elegans (Fig. 1A
). Binding assays revealed that netrin binds exclusively to the fifth fibronectin type III repeat of DCC and to the immunoglobulin repeat of UNC-5. A detailed analysis showed that disruption of the V-2 or V-3 domains of the nematode netrin ligand interferes with its ability to interact with the repulsion receptor, whereas its V-3 domain is involved in the interaction with the attraction receptor (6). Both DCC and UNC-5 bind to netrin with 1:1 stoichiometry, but their extracellular domains do not form a ternary complex between the ligand and the two receptors (7).

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Fig. 1. One Polypeptide Ligand Interacting with More Than One Receptor
A, Netrin interacts with DCC, UNC5, and integrins. Binding assays revealed that netrin binds exclusively to the fifth fibronectin type III repeat of DCC and to the immunoglobulin repeat of UNC5. Netrin ligand contains five distinct domains, designated VI, V-1, V-2, V-3, and C345C. VI is a typical N-terminal domain of laminin, V-1 through V-3 are epidermal growth factor-like domains, and C345C is a domain found also in complement proteins. Disrupting the V-2 or V-3 domains interferes with the ability of nematode netrin to interact with the UNC-5 receptor, whereas the V-3 domain is involved in the interaction with UNC-40. Both DCC and UNC5 bind to netrin with 1:1 stoichiometry, but their extracellular domains do not form a ternary complex between the ligand and the two receptors. Netrin also binds 6/ß4 and 3/ß1 integrin dimeric receptors. The specific domain in netrin that is critical to its binding and signaling through integrins is a small 25-amino acid residue long C-terminal region within C345C. B, Wnt ligands signal thorough the seven-transmembrane Frizzled receptors and the tyrosine kinase Derailed receptor. Dkk1 is the ligand for Kremen receptors and LRP5/6. EGF, Epidermal growth factor; TM, transmembrane; WIF, Wnt inhibitory factor; FN, fibronectin.
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Netrin is also found outside the nervous system. In epithelial tissues, netrin binds to
6/ß4 and
3/ß1 integrin dimeric receptors, through which it regulates the migration of putative pancreatic progenitors (8). The domain in netrin that is critical for integrin binding is a small C-terminal region, distinct from those for the other two receptors (9). Thus, netrin has three unrelated receptors to mediate its effect as a migratory cue, each interacting with a different protein domain of the ligand. All these receptors, as well as netrin itself, are present in metazoans.
Wnt Signals through Seven-Transmembrane and Atypical Tyrosine Kinase Receptors
Wnt is a ligand involved in D. melanogaster segmentation and wing formation, hence the null mutation was named wingless (10). In vertebrates, Wnt proteins are involved in the maintenance of morphological boundaries between distinct cellular populations (11, 12). Wnt ligands bind and activate the seven-transmembrane receptors, Frizzled (13, 14) (Fig. 1B
). Members of the Wnt-1 class activate the canonical pathway, thereby leading to an increase in cellular ß-catenin levels (15) that determine cell fate, whereas members of the Wnt-5a class (16) activate the noncanonical pathway (17) involved in cell shaping (14, 18). Wnt-5A, a cognate ligand for Frizzled5 (16, 19), was found also to activate an additional receptor, named Derailed (a member of the receptor tyrosine kinase, RYK, in mammals), during neuronal growth (20). Interestingly, Derailed is an atypical receptor tyrosine kinase without catalytic activity (21); its exact signaling mechanism is unclear. Thus, human Wnt-5A activates two unrelated receptors: Frizzled5 and Derailed. The Wnt family of ligands and the two types of receptors have their phylogenetic roots in early metazoans (19).
Dkk Binds Both Low-Density Lipoprotein Receptor-Related Protein (LRP) and Kremen
Wnt signaling is also modified by LRP5 and LRP6, both acting as coreceptors to Frizzled (Fig. 1B
). The secreted ligand Dickkopf1 (Dkk1) binds to and activates LRP5/6, which inhibit canonical Wnt signaling (22, 23). Interestingly, Dkk1 also binds to the transmembrane receptors Kremen1 and 2 (Fig. 1B
). Binding of the Dkk1/LRP5/6 complex to Kremen1 forms a ternary structure, inducing rapid endocytosis and removal of LRP5/6 from the plasma membrane (24, 25, 26). LRP5/6 appears to have a role in human bone homeostasis. A mutation in human LRP5 abolishes the ability of Dkk-1 to suppress Wnt signaling, leading to a hyperosteotic phenotype (27). Dkk and LRP5/6 are present in fly and nematode, suggesting metazoan origins. In contrast, Kremen1 and 2 have no orthologs in invertebrates. Thus, it is likely that Dkk originally was a ligand for LRP alone and later, during vertebrate evolution, also paired with Kremens (Table 1
).
Connective Tissue Growth Factor (CTGF) Binds Both LRP6 and Integrin-
5ß3
CTGF (also known as CCN2) is a hormone important in angiogenesis, chondrogenesis, and wound healing (28, 29). CTGF binds to the Wnt coreceptor LRP6 and therefore inhibits signaling through the Wnt pathway. In addition, CTGF induces hepatic stellate cell adhesion by binding to integrin-
5ß3 (30, 31) and also binds integrin-
Mß2 on peripheral blood monocytes (32). Thus, two unrelated receptor types interact with the same C-terminal cystine-knot module of CTGF. The rigid backbone of the cystine-knot structure of CTGF could expose key amino acid residues for receptor binding (33). Interestingly, CTGF also directly binds bone morphogenetic protein 4 and TGF-ß1 to regulate their binding to cognate receptors (34).
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THREE UNRELATED LIGANDS INTERACT WITH THE Nogo RECEPTOR
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In addition to LRP6, which interacts with two unrelated polypeptide ligands, CTGF and Dkk1, Nogo receptor is another rare example of one receptor activated by two or more unrelated ligands. The myelin components, Nogo-A, oligodendrocyte myelin glycoprotein, and myelin-associated glycoprotein, are unrelated protein ligands (35), all inhibiting neurite outgrowth by binding to the Nogo receptor (Fig. 2A
). The Nogo receptor is a glycosylphosphatidylinositol (GPI)-anchored extracellular protein that interacts with the coreceptor p75NTR for signal transduction (36, 37, 38). Like all GPI-linked proteins, Nogo receptor is vertebrate specific, and so is the p75 NTR gene that belongs to the TNF receptor family. All the three ligands are also vertebrate specific.

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Fig. 2. Multiple Ligands Share the Same Receptors and Select Receptors Share the Same Coreceptor
A, Nogo, myelin-associated glycoprotein (MAG), and oligodendrocyte myelin glycoprotein (OMGP) are all ligands for the Nogo receptor (NgR), which interacts with a coreceptor p75NTR. p75NTR is also a coreceptor to the Trk receptors known to interact with neurotrophins. B, Plexins, the receptors for semaphorins, and the VEGF receptor share the same coreceptor, neuropilin. C, GDNF binds to GFR- 1 which, in turn, forms complexes with either of the coreceptors RET or NCAM. VEGFR, VEGF receptor; TM, transmembrane; SP, serine protease; FN, fibronectin; Nrp, neuropilin.
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TWO RECEPTORS INTERACT WITH A COMMON CORECEPTOR
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In addition to the examples of multiple ligand-receptor partnerships, there are also examples of several receptors sharing the same coreceptor.
Trk Receptors and Nogo Share the Same Coreceptor p75 NTR
Neurotrophins selectively bind specific Trk receptors with tyrosine kinase activity [nerve growth factor to tyrosine receptor kinase A (TrkA), brain-derived neurotrophic factor to TrkB, and neurotrophin 3 to TrkC] (39). Downstream signaling by the neurotrophins is dependent on the recruitment of p75NTR, a member of the TNF receptor family (40, 41) (Fig. 2A
). Interestingly, p75NTR also serves as a coreceptor to the GPI-anchored Nogo receptor discussed above. The Trk tyrosine kinases are of metazoan origin whereas Nogo receptor and its three ligands, as well as p75NTR, are vertebrate specific. Thus, one vertebrate coreceptor p75NTR paired with two unrelated signaling systems, one involving the vertebrate-specific GPI-anchored Nogo receptor and one involving the Trk receptors of metazoan origin.
Plexins and Vascular Endothelial Growth Factor (VEGF) Receptors Use a Common Coreceptor, Neuropilin-1
Plexins are a large family of receptors for transmembrane, secreted, and GPI-anchored semaphorins (42, 43, 44). The exact cognate receptors for many semaphorins are not known. Both plexins and semaphorins contain a common sema domain, (43, 45), which is crucial for their biological activity (46, 47). Semaphorins were originally characterized in the nervous system and were implicated in axon guidance (48, 49, 50, 51, 52). They are also important in the development of bone, cartilage, heart (53), and the immune system (54, 55, 56). The activation of plexins by class 3 of secreted semaphorins involves neuropilin 1 and 2 (48, 49, 50), two transmembrane proteins with no apparent intracellular transduction activity (Fig. 2B
).
The VEGFs bind to VEGF receptors with tyrosine kinase activity. There are three VEGF receptors, each of which uses neuropilins as coreceptors (57, 58). Sharing of a common coreceptor allows cross-talk between the two unrelated ligand-receptor systems (59). Although VEGF receptors and plexins are of metazoan origin, neuropilins are vertebrate specific and may have become part of the two signaling mechanisms later in evolution.
The Glial Cell-Derived Neurotrophic Factor (GDNF) Receptor, GFR-
1, Signals through Both RET and Neural Cell Adhesion Molecule (NCAM)
GDNF regulates kidney morphogenesis, spermatogenesis, and neural development. GDNF binds to the GPI-linked GDNF family receptor-
1 (GFR-
1) without an intracellular domain (Fig. 2C
). The receptor-ligand complex further interacts with the coreceptor RET, a protooncogene mutated in patients with multiple endocrine neoplasia syndrome and Hircshsprung disease. Upon binding to the GDNF/GFR-
1 complexes, RET is activated in its intracellular tyrosine kinase domain (60). The cadherin-like domains in the extracellular region of RET are critical for its binding to both GDNF and GFR-
1 (61). GDNF also signals through a RET-independent pathway (62) by activating heterodimers of GFR-
and NCAM (63). This pathway regulates Schwann cell migration and axonal growth in hippocampal and cortical neurons (63, 64, 65).
NCAM and RET are of metazoan origin, whereas GDNF and the GFR-
1 have no orthologs outside the vertebrates. Thus, the vertebrate-specific complexes between GDNF and GFR-
1 paired with two unrelated coreceptors of earlier origins.
In summary, there are several polypeptide ligands that bind and activate more than one receptor and vice versa. In some cases one ligand-receptor (or receptor-coreceptor) pairing appears to have occurred earlier during evolution. Sequential pairings of a new partner for signaling are rare events because the relationships between the respective protein pairs are locked. When one ligand binds two receptors, coevolutionary changes of the polypeptide ligand with one receptor could easily disrupt its locked pairing with the other partner. With further structural analyses of the interfaces between these polypeptide ligand-receptor pairs, it is important to investigate the evolution of different domains in these genes.
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NONPEPTIDE NEUROTRANSMITTERS INTERACT WITH BOTH CHANNEL AND PLASMA MEMBRANE RECEPTORS
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In contrast to the rare partnering among protein ligands with receptors and coreceptors, there are many examples of one small ligand interacting with two or more receptor types. Among these there are many neurotransmitters, capable of activating both plasma membrane G protein-coupled receptors (GPCRs) and ligand-gated channels. Some also paired with an independent transporter protein (Table 1
).
Acetylcholine (Ach) Activates Both Nicotinic (Channel Type) and Muscarinic (Seven-Transmembrane Type) Receptors
ACh released from the motor nerve terminal diffuses across the synaptic cleft where it binds to nicotinic receptors in the muscle and triggers the opening of the sodium channel receptor. The nicotinic channel receptor is a pentamer with a long, cylindrical structure that surrounds a central ion permeation pore. Each receptor consists of two
-subunits and a combination of three other subunits. There are five known subunits in the muscle-type nicotinic ACh receptors (
1, ß1,
,
, and
) and 12 in the neuronal-type nicotinic Ach receptors (
2
10 and ß2, ß3, and ß4). Some neuronal nicotinic Ach receptors are also functional as homopentamers. Each subunit is a four-transmembrane protein, of which the second helix forms the pore (66). The muscarinic ACh receptors are type A GPCRs. There are five receptor subtypes of which the M1, M3, and M5 couple preferentially to G proteins of the Gq/G11 class, leading to phosphoinositide breakdown. In contrast, M2 and M4 couple to G proteins of the Gi and Go classes, leading to adenylate cyclase inhibition (67).
The channel-type ACh receptor is of prokaryotic origin, whereas the muscarinic receptor and the choline acyltransferase for acetylcholine biosynthesis are of metazoan origin (Table 1
). There is no sequence homology between the nicotinic and the muscarinic receptors, and it is likely that the pairing of these two receptor types with ACh occurred independently.
-Aminobutyric Acid (GABA) Activates Channels and Seven-Transmembrane Receptors
GABA, derived from the decarboxylation of L-glutamate, is the major inhibitory neurotransmitter found in the brain. GABA binds to three groups of receptors: GABAA, GABAB, and GABAC. GABAA receptors are heteropentameric chloride channels consisting of monomers with four-transmembrane sequences. The GABAB receptors are GPCRs. The ligand-binding site of these receptors has been likened to a Venus flytrap due to their bulky ectodomains that form two lobes wrapping around GABA upon binding (68, 69). There is no sequence similarity between the ligand-binding domains of GABAA and GABAB receptors. The GABAC receptors are homooligomers of
1,
2, and
3 subunits, which are paralogous to the units composing the GABAA receptors (70). Thus, GABA pairs with two types of receptors, one with channel function and one with G protein-coupling ability.
GABA was initially identified as a metabolic product in bacteria, fungi, and plants before its discovery in the brain (71), suggesting an ancient evolutionary origin of its synthetic pathway. Indeed, there are bacterial orthologs for the human glutamate decarboxylase enzyme. We also identified bacterial orthologs for the GABAA subunits with conservation of the four-transmembrane structure. Therefore, it appears that both the channel and the penultimate synthetic enzyme for GABA have prokaryotic origins. In contrast, seven-transmembrane receptors appeared in eukaryotes (Table 1
). Interestingly, the colony-forming amoeboid slime mold Dictyostelium discoideum has an ortholog for GABAB receptors. It is likely, that the interaction between GABA and the GABAB receptors occurred later in evolution than GABAs interaction with the channels.
Glutamate Activates Ionotrophic Channel Receptors and Metabotrophic Seven-Transmembrane Receptors and Gates the Channel Activity of Its Cognate Transporter
Based on their pharmacological properties, ionotrophic glutamate receptors (iGluRs) are subdivided into three groups: a-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptors, kainite receptors, and N-methyl-D-aspartate receptors. They are ligand-gated tetrameric channels with four-transmembrane domains (72), the specific ion conductivity of which is defined by the subunit composition of the tetramer (73). Another set of glutamate receptors, termed metabotrophic (mGluR), are GPCRs. The ligand-binding N-terminal domain of mGluR is homologous to that of the iGluR and shares the same principle of allosteric activation. Glutamate binding to these receptors leads to G protein activation (74).
A third partner for glutamate is the transporter excitatory amino acid transporter 1 with an anion channel property, partially independent of its role as a transporter. A point mutation can block the transporter function of excitatory amino acid transporter 1 but does not affect glutamate-gated anion conductance. However, the glutamate recognition site in this transporter bears no homology to the other two types of receptors. Thus, the small neurotransmitter glutamate interacts with three types of receptors.
Orthologs for the glutamate transporters are present in prokaryotes (75). Likewise, the ectodomain of the mGluR and the ligand-binding region of iGluRs are homologous to bacterial proteins (76, 77). There are also GluRs in plants which further support the ancient origin of this domain (78). It is likely that the ligand recognition domain of the iGluR has become connected to a mGluR GPCR by an event of domain shuffling, but the ligand recognition site in the transporter has emerged independently.
Serotonin (5-HT) Activates Both Channels and Seven-Transmembrane Receptors and Has a Cognate Transporter
5-HT (5-hydroxytryptamine) is a potent vasoconstrictor in the general circulation (79). 5-HT receptors are major targets for drug development due to their role in affective disorders, vascular tone, and gastrointestinal function. There are seven 5-HT receptor classes (5-HT1 through 5-HT7), the 5-HT3 receptors being ligand-gated calcium channels, whereas all others are GPCRs (80, 81). The channel-type 5-HT3 receptor has two subunits: 5-HT3A and 5-HT3B. The 5-HT3A forms functional homooligomers (82), whereas the 5-HT3B is functional only after heterooligomerization (83). 5-HT interacts with a third type of integral membrane protein, the 5-HT transporter. This is a 12-transmembrane domain protein that cotransports sodium with 5-HT (84). It is the target for drugs that prevent reuptake of secreted 5-HT (85).
The 5-HT3 channel and 5-HT transporter have orthologs in the bacteria. Several bacteria also have the penultimate enzyme for 5-HT synthesis, aromatic-L-amino acid decarboxylase. In contrast, orthologs for the seven-transmembrane 5-HT receptors can be found in the fly and the nematode but not in yeast. Thus, there does not appear to be a common phylogeny to the three types of interacting proteins. The pairing events of 5-HT with the two receptor types and the transporter are likely to be independent of each other.
ATP Activates Channel-Type And Seven-Transmembrane GPCRs
In addition to being an intracellular energy source for all cells, extracellular ATP activates two types of receptors. P2X receptors are nonselective cation channels, whereas P2Y receptors are GPCRs (86). P2Xs are activated exclusively by ATP, whereas some P2Ys are activated also by UTP, UDP, or ADP. Similar to other neurotransmitters, ATP is released by neurons in granules (87). In addition, ATP is also released from intact cells in nonexcitable tissues after mechanical or pharmacological stimulations.
P2Xs are two-transmembrane proteins, with cytoplasmic N- and C termini. The first transmembrane domain participates in the agonist-induced gating of the channel (88), and part of the pore is formed by the second hydrophobic domain (89). Each of the seven identified mammalian subunit proteins, except P2X6, can form functional homooligomeric channels and all, except P2X7, can form heterooligomers (90). In contrast, P2Y receptors are coupled to phospholipase C via Gq proteins but, in some cases, P2Y receptors also signal through the Gi pathway, which inhibits cellular cAMP production (91). In the neuromuscular synapses, ATP induces the expression of muscle ACh receptor and acetylcholinesterase through P2Y1 receptors (92).
P2Y receptors are of vertebrate origin (93). We did not find any orthologs for the P2X channel proteins in the fly, nematode, or the sea squirt Ciona intestinalis, indicating that they are also of vertebrate origin. Because purines are synthesized in prokaryotes but P2X and P2Y are found only in vertebrates, it is likely that the pairing of this ubiquitous cell metabolite with channels and plasma membrane receptors occurred during vertebrate evolution.
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LIPOID LIGANDS GATE CHANNELS AND ACTIVATE PLASMA MEMBRANE AND NUCLEAR RECEPTORS
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Lipids, which freely penetrate biological membranes, have the potential to interact with intracellular proteins such as transcription factors (nuclear receptors) in addition to plasma membrane receptors. Some lipid ligands gate channels and activate seven-transmembrane receptors, nuclear receptors, and cognate transporters (Table 1
).
Anandamide Gates the Vanilloid Receptor (VR)1 Channel and Activates G Protein-Coupled Cannabinoid (CB) Receptors
Arachidonylethanolamide (anandamide) is an inflammatory mediator, derived by phosphodiesterase-mediated cleavage of N-arachidonoyl-phosphatidylethanolamine (94, 95, 96). Anandamide activates a nonselective cation channel receptor named VR1 as well as two CB GPCRs named CB1 and CB2. VR1 belongs to the TRPV subfamily within a family of channels designated TRP for transient receptor potential. TRPs consist of four subunits, each with six-transmembrane domains and a reentrant loop between transmembrane spans 5 and 6. The four reentrant loops line the cation channel. VR1 is also gated by pressure, extreme temperatures (97, 98), and capsaicin (the substance making chili peppers "hot"). The GPCRs for anandamide, CB1 or CB2, transduce signals by activation of G(i/o) proteins which mediate inhibition of adenylyl cyclase and downstream events (99).
The yeast has an ortholog for phospholipase D, the penultimate enzyme in anandamide biosynthesis. VR1 has orthologs only in metazoans (nematode and fly) and CBs are chordate specific because they have an ortholog in C. intestinalis (100). Thus, anandamide most likely paired with its two unrelated receptors sequentially during the emergence of metazoans and chordates.
Progesterone Gates Ion Channels and Activates Both a Seven-Transmembrane Receptor and a Nuclear Receptor
The steroid hormone progesterone is known primarily for activating its cognate nuclear receptor. Upon binding of progesterone to this intracellular receptor, the complex exerts direct effects on DNA transcription. This receptor belongs to a superfamily of ligand-activated transcription factors (101). In addition to activating a nuclear steroid receptor, progesterone also activates a seven-transmembrane receptor (Fig. 3
). After the identification of the progestin membrane receptor in spotted sea trout (102), many orthologous receptors were found in vertebrates (103). The recombinant human
- and
-progestin receptors were shown to bind progesterone with high specificity and affinity.

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Fig. 3. Progesterone Activates Three Receptors, Each of Which Arose at a Different Stage of Evolution
BYA, Billion years ago.
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Progesterone is also neuroactive because it acts as a functional antagonist at the channel-type 5-HT receptor (5-HT3) (104). Progesterone probably interacts allosterically with the 5-HT3 receptor at the receptor-lipid bilayer interface and not at the 5-HT-binding pocket (105). In addition, progesterone also inhibits brain nicotinic acetylcholine receptors by interacting with a site located on the extracellular part of the channel receptor. The inhibition by progesterone is likely not the result of nonspecific perturbation of the membrane bilayer or second messenger activation (106). It is interesting to note that steroid derivatives are also ligands for plant receptors with disparate origins from animal receptors (107, 108).
Nuclear steroid hormone receptors are vertebrate specific, but the chordate, C. intestinalis, has orthologs for the penultimate biosynthetic enzyme for progesterone and the GPCR for progesterone. Thus, the pairing between progesterone and the GPCR likely occurred before progesterones partnership with a nuclear receptor.
Catabolic Products of Membrane Phospholipids Activate Multiple Types of Receptors
Catabolism of membrane phospholipids yields several products, among which are free fatty acids, lysophosphatidic acid (LPA), and prostaglandins. Like progesterone, free fatty acids also activate three types of receptors (109, 110, 111). In addition, fatty acids interact with a membrane transporter (112) (Table 1
). Although LPA is known to activate a set of seven-transmembrane receptors called EDG 17 (113), it also interacts with two nuclear receptors, peroxisome proliferator-activated receptor-
and LPA1R (114, 115). One of the prostaglandins, prostaglandin D, activates the nuclear peroxisome proliferator-activated receptor-
and the GPCR prostaglandin D2 receptor (116, 117). It is also transported into the cell by a transporter, prostaglandin transporter (118). Several other catabolic products of membrane phospholipids activate more than one receptor type (119, 120). The possibility of direct activation of channels, without the mediation of a GPCR, is supported by experimental data showing that lysophosphatidyl choline-mediated calcium mobilization involves an as-yet-unknown lysophosphatidyl choline receptor using a G protein-independent signaling pathway (121).
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ITS A SMALL (LIGAND) WORLD AFTER ALL
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The observation that many ligands are paired with more than one receptor type highlights the utilitarian use of a limited number of cellular components during metazoan evolution. Some derivatives of nutrients, metabolites, and nucleic acids are initially cellular waste products, but their unique chemical properties allowed pairing with plasma membrane channels and receptors as well as nuclear transcriptional factors. In contrast to protein ligands with restricted adaptability, ligands that are catalytic products of essential enzymes remain fixed. The continuous presence of these ligands, including neurotransmitters and lipoid compounds, during evolution increased their chance of pairing with a second receptor. One can ask whether other small metabolites (e.g. secreted nucleotides and amino acid derivatives) known to be ligands for GPCRs could also be ligands for channels. Alternatively, lipid-soluble molecules for known nuclear receptors (T4, vitamin D, etc.) could be tested as candidate ligands for GPCRs and channels. Indeed, many orphan GPCRs and nuclear receptor paralogs still await the discovery of their cognate ligands. Future research could reveal whether some of them interact with ligands currently known to modulate other receptors. Furthermore, more than 15% of the human genome consists of genes with predictable transmembrane domains; some of them are also candidates for interaction with the small group of evolutionarily conserved ligands. High throughput screening of receptor agonists and antagonists is likely to be more productive when the candidate drugs are modeled after the structures of these ligands. Understanding the structural basis of the interactions between these conserved ligands and their multiple receptors should be a high priority for future research.
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FOOTNOTES
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This work was supported by National Institutes of Health Grant HD23273.
First Published Online February 3, 2005
Abbreviations: ACh, Acetylcholine; CB, cannabinoid; CTGF, connective tissue growth factor; DCC, deleted in colorectal carcinoma; Dkk1, Dickkopf1; GABA,
-aminobutyric acid; GDNF, glial cell-derived neurotrophic factor; GFR-
1, GDNF family receptor-
1; GPCR, G protein-coupled receptor; GPI, glycosylphosphatidylinositol; 5-HT, serotonin; iGluR, ionotrophic glutamate receptor; LPA, lysophosphatidic acid; LRP, low-density lipoprotein receptor-related protein; mGluR, metabotrophic glutamate receptor; NCAM, neural cell adhesion molecule; TrkA, tyrosine receptor kinase A; TRP, transient receptor potential; VEGF, vascular endothelial growth factor; VR, vanilloid receptor
Received for publication November 8, 2004.
Accepted for publication January 27, 2005.
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REFERENCES
|
---|
- Gao Z, Metz WA 2003 Unraveling the chemistry of chemokine receptor ligands. Chem Rev 103:37333752[CrossRef][Medline]
- Livesey FJ, Hunt SP 1997 Netrin and netrin receptor expression in the embryonic mammalian nervous system suggests roles in retinal, striatal, nigral, and cerebellar development. Mol Cell Neurosci 8:417429[CrossRef][Medline]
- Livesey FJ 1999 Netrins and netrin receptors. Cell Mol Life Sci 56:6268[CrossRef][Medline]
- Hjorth JT, Gad J, Cooper H, Key B 2001 A zebrafish homologue of deleted in colorectal cancer (zdcc) is expressed in the first neuronal clusters of the developing brain. Mech Dev 109:105109[CrossRef][Medline]
- Johansson K, Torngren M, Wasselius J, Mansson L, Ehinger B 2001 Developmental expression of DCC in the rat retina. Brain Res Dev Brain Res 130:133138[Medline]
- Lim YS, Wadsworth WG 2002 Identification of domains of netrin UNC-6 that mediate attractive and repulsive guidance and responses from cells and growth cones. J Neurosci 22:70807087[Abstract/Free Full Text]
- Geisbrecht BV, Dowd KA, Barfield RW, Longo PA, Leahy DJ 2003 Netrin binds discrete subdomains of DCC and UNC5 and mediates interactions between DCC and heparin. J Biol Chem 278:3256132568[Abstract/Free Full Text]
- Yebra M, Montgomery AM, Diaferia GR, Kaido T, Silletti S, Perez B, Just ML, Hildbrand S, Hurford R, Florkiewicz E, Tessier-Lavigne M, Cirulli V 2003 Recognition of the neural chemoattractant Netrin-1 by integrins
6ß4 and
3ß1 regulates epithelial cell adhesion and migration. Dev Cell 5:695707[CrossRef][Medline]
- Kennedy TE, Serafini T, de la Torre JR, Tessier-Lavigne M 1994 Netrins are diffusible chemotropic factors for commissural axons in the embryonic spinal cord. Cell 78:425435[CrossRef][Medline]
- Klingensmith J, Nusse R 1994 Signaling by wingless in Drosophila. Dev Biol 166:396414[CrossRef][Medline]
- Pourquie O 2003 The segmentation clock: converting embryonic time into spatial pattern. Science 301:328330[Abstract/Free Full Text]
- Vainio S, Heikkila M, Kispert A, Chin N, McMahon AP 1999 Female development in mammals is regulated by Wnt-4 signalling. Nature 397:405409[CrossRef][Medline]
- Ingham PW 1996 Has the quest for a Wnt receptor finally frizzled out? Trends Genet 12:382384[CrossRef][Medline]
- Moon RT 2004 Teaching resource. Canonical Wnt/ß-catenin signaling. Sci STKE 2004:tr5.
- Martinez Arias A 2000 The informational content of gradients of Wnt proteins. Sci STKE 2000:PE1.
- He X, Saint-Jeannet JP, Wang Y, Nathans J, Dawid I, Varmus H 1997 A member of the Frizzled protein family mediating axis induction by Wnt-5A. Science 275:16521654[Abstract/Free Full Text]
- Maye P, Zheng J, Li L, Wu D 2004 Multiple mechanisms for Wnt11-mediated repression of the canonical Wnt signaling pathway. J Biol Chem 279:2465924665[Abstract/Free Full Text]
- Rothbacher U, Lemaire P 2002 Creme de la Kremen of Wnt signalling inhibition. Nat Cell Biol 4:E172E173
- Prudhomme B, Lartillot N, Balavoine G, Adoutte A, Vervoort M 2002 Phylogenetic analysis of the Wnt gene family. Insights from lophotrochozoan members. Curr Biol 12:1395[CrossRef][Medline]
- Yoshikawa S, McKinnon RD, Kokel M, Thomas JB 2003 Wnt-mediated axon guidance via the Drosophila Derailed receptor. Nature 422:583588[CrossRef][Medline]
- Yoshikawa S, Bonkowsky JL, Kokel M, Shyn S, Thomas JB 2001 The derailed guidance receptor does not require kinase activity in vivo. J Neurosci 21:RC119
- Semenov MV, Tamai K, Brott BK, Kuhl M, Sokol S, He X 2001 Head inducer Dickkopf-1 is a ligand for Wnt coreceptor LRP6. Curr Biol 11:951961[CrossRef][Medline]
- Bafico A, Liu G, Yaniv A, Gazit A, Aaronson SA 2001 Novel mechanism of Wnt signalling inhibition mediated by Dickkopf-1 interaction with LRP6/Arrow. Nat Cell Biol 3:683686[CrossRef][Medline]
- Mao B, Wu W, Davidson G, Marhold J, Li M, Mechler BM, Delius H, Hoppe D, Stannek P, Walter C, Glinka A, Niehrs C 2002 Kremen proteins are Dickkopf receptors that regulate Wnt/ß-catenin signalling. Nature 417:664667[CrossRef][Medline]
- Mao B, Niehrs C 2003 Kremen2 modulates Dickkopf2 activity during Wnt/LRP6 signaling. Gene 302:179183[CrossRef][Medline]
- Brott BK, Sokol SY 2002 Regulation of Wnt/LRP signaling by distinct domains of Dickkopf proteins. Mol Cell Biol 22:61006110[Abstract/Free Full Text]
- Boyden LM, Mao J, Belsky J, Mitzner L, Farhi A, Mitnick MA, Wu D, Insogna K, Lifton RP 2002 High bone density due to a mutation in LDL-receptor-related protein 5. N Engl J Med 346:15131521[Abstract/Free Full Text]
- Chang C, Holtzman DA, Chau S, Chickering T, Woolf EA, Holmgren LM, Bodorova J, Gearing DP, Holmes WE, Brivanlou AH 2001 Twisted gastrulation can function as a BMP antagonist. Nature 410:483487[CrossRef][Medline]
- Mercurio S, Latinkic B, Itasaki N, Krumlauf R, Smith JC 2004 Connective-tissue growth factor modulates WNT signalling and interacts with the WNT receptor complex. Development 131:21372147[Abstract/Free Full Text]
- Babic AM, Chen CC, Lau LF 1999 Fisp12/mouse connective tissue growth factor mediates endothelial cell adhesion and migration through integrin
vß3, promotes endothelial cell survival, and induces angiogenesis in vivo. Mol Cell Biol 19:29582966[Abstract/Free Full Text]
- Gao R, Brigstock DR 2004 Connective tissue growth factor (CCN2) induces adhesion of rat activated hepatic stellate cells by binding of its C-terminal domain to integrin
(v)ß(3) and heparan sulfate proteoglycan. J Biol Chem 279:88488855[Abstract/Free Full Text]
- Schober JM, Chen N, Grzeszkiewicz TM, Jovanovic I, Emeson EE, Ugarova TP, Ye RD, Lau LF, Lam SC 2002 Identification of integrin
(M)ß(2) as an adhesion receptor on peripheral blood monocytes for Cyr61 (CCN1) and connective tissue growth factor (CCN2): immediate-early gene products expressed in atherosclerotic lesions. Blood 99:44574465[Abstract/Free Full Text]
- Vitt UA, Hsu SY, Hsueh AJ 2001 Evolution and classification of cystine knot-containing hormones and related extracellular signaling molecules. Mol Endocrinol 15:681694[Abstract/Free Full Text]
- Abreu JG, Ketpura NI, Reversade B, De Robertis EM 2002 Connective-tissue growth factor (CTGF) modulates cell signalling by BMP and TGF-beta. Nat Cell Biol 4:599604[Medline]
- Hunt D, Coffin RS, Anderson PN 2002 The Nogo receptor, its ligands and axonal regeneration in the spinal cord; a review. J Neurocytol. 31:93120
- Liu BP, Fournier A, GrandPre T, Strittmatter SM 2002 Myelin-associated glycoprotein as a functional ligand for the Nogo-66 receptor. Science 297:11901193[Abstract/Free Full Text]
- Wang KC, Koprivica V, Kim JA, Sivasankaran R, Guo Y, Neve RL, He Z 2002 Oligodendrocyte-myelin glycoprotein is a Nogo receptor ligand that inhibits neurite outgrowth. Nature 417:941944[CrossRef][Medline]
- Fournier AE, GrandPre T, Strittmatter SM 2001 Identification of a receptor mediating Nogo-66 inhibition of axonal regeneration. Nature 409:341346[CrossRef][Medline]
- Ivanisevic L, Banerjee K, Saragovi HU 2003 Differential cross-regulation of TrkA and TrkC tyrosine kinase receptors with p75. Oncogene 22:56775685[CrossRef][Medline]
- Lee FS, Kim AH, Khursigara G, Chao MV 2001 The uniqueness of being a neurotrophin receptor. Curr Opin Neurobiol 11:281286[CrossRef][Medline]
- Wong ST, Henley JR, Kanning KC, Huang KH, Bothwell M, Poo MM 2002 A p75(NTR) and Nogo receptor complex mediates repulsive signaling by myelin-associated glycoprotein. Nat Neurosci 5:13021308[CrossRef][Medline]
- Tamagnone L, Artigiani S, Chen H, He Z, Ming GI, Song H, Chedotal A, Winberg ML, Goodman CS, Poo M, Tessier-Lavigne M, Comoglio PM 1999 Plexins are a large family of receptors for transmembrane, secreted, and GPI-anchored semaphorins in vertebrates. Cell 99:7180[CrossRef][Medline]
- Kolodkin AL, Matthes DJ, Goodman CS 1993 The semaphorin genes encode a family of transmembrane and secreted growth cone guidance molecules. Cell 75:13891399[CrossRef][Medline]
- 1999 Unified nomenclature for the semaphorins/collapsins. Semaphorin Nomenclature Committee. Cell 97:551552
- Winberg ML, Noordermeer JN, Tamagnone L, Comoglio PM, Spriggs MK, Tessier-Lavigne M, Goodman CS 1998 Plexin A is a neuronal semaphorin receptor that controls axon guidance. Cell 95:903916[CrossRef][Medline]
- Giger RJ, Urquhart ER, Gillespie SK, Levengood DV, Ginty DD, Kolodkin AL 1998 Neuropilin-2 is a receptor for semaphorin IV: insight into the structural basis of receptor function and specificity. Neuron 21:10791092[CrossRef][Medline]
- Nakamura F, Tanaka M, Takahashi T, Kalb RG, Strittmatter SM 1998 Neuropilin-1 extracellular domains mediate semaphorin D/III-induced growth cone collapse. Neuron 21:10931100[CrossRef][Medline]
- Chen H, Chedotal A, He Z, Goodman CS, Tessier-Lavigne M 1997 Neuropilin-2, a novel member of the neuropilin family, is a high affinity receptor for the semaphorins Sema E and Sema IV but not Sema III. Neuron 19:547559[CrossRef][Medline]
- He Z, Tessier-Lavigne M 1997 Neuropilin is a receptor for the axonal chemorepellent semaphorin III. Cell 90:739751[CrossRef][Medline]
- Kolodkin AL, Levengood DV, Rowe EG, Tai YT, Giger RJ, Ginty DD 1997 Neuropilin is a semaphorin III receptor. Cell 90:753762[CrossRef][Medline]
- Pasterkamp RJ, De Winter F, Giger RJ, Verhaagen J 1998 Role for semaphorin III and its receptor neuropilin-1 in neuronal regeneration and scar formation? Prog Brain Res 117:151170[Medline]
- Artigiani S, Comoglio PM, Tamagnone L 1999 Plexins, semaphorins, and scatter factor receptors: a common root for cell guidance signals? IUBMB Life 48:477482[CrossRef][Medline]
- Behar O, Golden JA, Mashimo H, Schoen FJ, Fishman MC 1996 Semaphorin III is needed for normal patterning and growth of nerves, bones and heart. Nature 383:525528[CrossRef][Medline]
- Hall KT, Boumsell L, Schultze JL, Boussiotis VA, Dorfman DM, Cardoso AA, Bensussan A, Nadler LM, Freeman GJ 1996 Human CD100, a novel leukocyte semaphorin that promotes B-cell aggregation and differentiation. Proc Natl Acad Sci USA 93:1178011785[Abstract/Free Full Text]
- Delaire S, Elhabazi A, Bensussan A, Boumsell L 1998 CD100 is a leukocyte semaphorin. Cell Mol Life Sci 54:12651276[CrossRef][Medline]
- Delaire S, Billard C, Tordjman R, Chedotal A, Elhabazi A, Bensussan A, Boumsell L 2001 Biological activity of soluble CD100. II. Soluble CD100, similarly to H-SemaIII, inhibits immune cell migration. J Immunol 166:43484354[Abstract/Free Full Text]
- Soker S, Takashima S, Miao HQ, Neufeld G, Klagsbrun M 1998 Neuropilin-1 is expressed by endothelial and tumor cells as an isoform-specific receptor for vascular endothelial growth factor. Cell 92:735745[CrossRef][Medline]
- Matsumoto T, Claesson-Welsh L 2001 VEGF receptor signal transduction. Sci STKE 2001:RE21
- Castro-Rivera E, Ran S, Thorpe P, Minna JD 2004 Semaphorin 3B (SEMA3B) induces apoptosis in lung and breast cancer, whereas VEGF165 antagonizes this effect. Proc Natl Acad Sci USA 101:1143211437[Abstract/Free Full Text]
- Popsueva A, Poteryaev D, Arighi E, Meng X, Angers-Loustau A, Kaplan D, Saarma M, Sariola H 2003 GDNF promotes tubulogenesis of GFR
1-expressing MDCK cells by Src-mediated phosphorylation of Met receptor tyrosine kinase. J Cell Biol 161:119129[Abstract/Free Full Text]
- Kjaer S, Ibanez CF 2003 Identification of a surface for binding to the GDNF-GFR
1 complex in the first cadherin-like domain of RET. J Biol Chem 278:4789847904[Abstract/Free Full Text]
- Trupp M, Belluardo N, Funakoshi H, Ibanez CF 1997 Complementary and overlapping expression of glial cell line-derived neurotrophic factor (GDNF), c-ret proto-oncogene, and GDNF receptor-
indicates multiple mechanisms of trophic actions in the adult rat CNS. J Neurosci 17:35543567[Abstract/Free Full Text]
- Paratcha G, Ledda F, Ibanez CF 2003 The neural cell adhesion molecule NCAM is an alternative signaling receptor for GDNF family ligands. Cell 113:867879[CrossRef][Medline]
- Crossin KL, Krushel LA 2000 Cellular signaling by neural cell adhesion molecules of the immunoglobulin superfamily. Dev Dyn 218:260279[CrossRef][Medline]
- Ronn LC, Berezin V, Bock E 2000 The neural cell adhesion molecule in synaptic plasticity and ageing. Int J Dev Neurosci 18:193199[CrossRef][Medline]
- Capener CE, Kim HJ, Arinaminpathy Y, Sansom MS 2002 Ion channels: structural bioinformatics and modelling. Hum Mol Genet 11:24252433[Abstract/Free Full Text]
- Hulme EC, Lu ZL, Saldanha JW, Bee MS 2003 Structure and activation of muscarinic acetylcholine receptors. Biochem Soc Trans 31:2934[Medline]
- Galvez T, Parmentier ML, Joly C, Malitschek B, Kaupmann K, Kuhn R, Bittiger H, Froestl W, Bettler B, Pin JP 1999 Mutagenesis and modeling of the GABAB receptor extracellular domain support a venus flytrap mechanism for ligand binding. J Biol Chem 274:1336213369[Abstract/Free Full Text]
- Galvez T, Prezeau L, Milioti G, Franek M, Joly C, Froestl W, Bettler B, Bertrand HO, Blahos J, Pin JP 2000 Mapping the agonist-binding site of GABAB type 1 subunit sheds light on the activation process of GABAB receptors. J Biol Chem 275:4116641174[Abstract/Free Full Text]
- Johnston GA 2002 Medicinal chemistry and molecular pharmacology of GABA(C) receptors. Curr Top Med Chem 2:903913[CrossRef][Medline]
- Wassef A, Baker J, Kochan LD 2003 GABA and schizophrenia: a review of basic science and clinical studies. J Clin Psychopharmacol 23:601640[CrossRef][Medline]
- Ayalon G, Stern-Bach Y 2001 Functional assembly of AMPA and kainate receptors is mediated by several discrete protein-protein interactions. Neuron 31:103113[CrossRef][Medline]
- Madden DR 2002 The structure and function of glutamate receptor ion channels. Nat Rev Neurosci 3:91101[CrossRef][Medline]
- Kunishima N, Shimada Y, Tsuji Y, Sato T, Yamamoto M, Kumasaka T, Nakanishi S, Jingami H, Morikawa K 2000 Structural basis of glutamate recognition by a dimeric metabotropic glutamate receptor. Nature 407:971977[CrossRef][Medline]
- Kanner BI, Kavanaugh MP, Bendahan A 2001 Molecular characterization of substrate-binding sites in the glutamate transporter family. Biochem Soc Trans 29:707710[CrossRef][Medline]
- OHara PJ, Sheppard PO, Thogersen H, Venezia D, Haldeman BA, McGrane V, Houamed KM, Thomsen C, Gilbert TL, Mulvihill ER 1993 The ligand-binding domain in metabotropic glutamate receptors is related to bacterial periplasmic binding proteins. Neuron 11:4152[CrossRef][Medline]
- Chen GQ, Cui C, Mayer ML, Gouaux E 1999 Functional characterization of a potassium-selective prokaryotic glutamate receptor. Nature 402:817821[CrossRef][Medline]
- Chiu J, DeSalle R, Lam HM, Meisel L, Coruzzi G 1999 Molecular evolution of glutamate receptors: a primitive signaling mechanism that existed before plants and animals diverged. Mol Biol Evol 16:826838[Abstract]
- Reeves DC, Lummis SC 2002 The molecular basis of the structure and function of the 5-HT3 receptor: a model ligand-gated ion channel (review). Mol Membr Biol 19:1126[CrossRef][Medline]
- Glennon RA 2003 Higher-end serotonin receptors: 5-HT(5), 5-HT(6), and 5-HT(7). J Med Chem 46:27952812[CrossRef][Medline]
- Saxena PR 1995 Serotonin receptors: subtypes, functional responses and therapeutic relevance. Pharmacol Ther 66:339368[CrossRef][Medline]
- Jackson MB, Yakel JL 1995 The 5-HT3 receptor channel. Annu Rev Physiol 57:447468[CrossRef][Medline]
- Davies PA, Pistis M, Hanna MC, Peters JA, Lambert JJ, Hales TG, Kirkness EF 1999 The 5-HT3B subunit is a major determinant of serotonin-receptor function. Nature 397:359363[CrossRef][Medline]
- Saier Jr MH 1999 A functional-phylogenetic system for the classification of transport proteins. J Cell Biochem (Suppl 3233):8494
- Torres GE, Gainetdinov RR, Caron MG 2003 Plasma membrane monoamine transporters: structure, regulation and function. Nat Rev Neurosci 4:1325[CrossRef][Medline]
- Khakh BS 2001 Molecular physiology of P2X receptors and ATP signalling at synapses. Nat Rev Neurosci 2:165174[CrossRef][Medline]
- Lazarowski ER, Boucher RC, Harden TK 2003 Mechanisms of release of nucleotides and integration of their action as P2X- and P2Y-receptor activating molecules. Mol Pharmacol 64:785795[Free Full Text]
- Haines WR, Migita K, Cox JA, Egan TM, Voigt MM 2001 The first transmembrane domain of the P2X receptor subunit participates in the agonist-induced gating of the channel. J Biol Chem 276:3279332798[Abstract/Free Full Text]
- Rassendren F, Buell G, Newbolt A, North RA, Surprenant A 1997 Identification of amino acid residues contributing to the pore of a P2X receptor. EMBO J 16:34463454[Abstract/Free Full Text]
- Torres GE, Egan TM, Voigt MM 1999 Hetero-oligomeric assembly of P2X receptor subunits. Specificities exist with regard to possible partners. J Biol Chem 274:66536659[Abstract/Free Full Text]
- Song SL, Chueh SH 1996 P2 purinoceptor-mediated inhibition of cyclic AMP accumulation in NG10815 cells. Brain Res 734:243251[CrossRef][Medline]
- Tsim KW, Barnard EA 2002 The signaling pathways mediated by P2Y nucleotide receptors in the formation and maintenance of the skeletal neuromuscular junction. Neurosignals 11:5864[CrossRef][Medline]
- Schulz A, Schoneberg T 2003 The structural evolution of a P2Y-like G-protein-coupled receptor. J Biol Chem 278:3553135541[Abstract/Free Full Text]
- Iversen L 1994 Pharmacology. Endogenous cannabinoids. Nature 372:619[CrossRef][Medline]
- Sugiura T, Kondo S, Sukagawa A, Tonegawa T, Nakane S, Yamashita A, Waku K 1996 Enzymatic synthesis of anandamide, an endogenous cannabinoid receptor ligand, through N-acylphosphatidylethanolamine pathway in testis: involvement of Ca(2+)-dependent transacylase and phosphodiesterase activities. Biochem Biophys Res Commun 218:113117[CrossRef][Medline]
- Koutek B, Prestwich GD, Howlett AC, Chin SA, Salehani D, Akhavan N, Deutsch DG 1994 Inhibitors of arachidonoyl ethanolamide hydrolysis. J Biol Chem 269:2293722940[Abstract/Free Full Text]
- Kim J, Chung YD, Park DY, Choi S, Shin DW, Soh H, Lee HW, Son W, Yim J, Park CS, Kernan MJ, Kim C 2003 A TRPV family ion channel required for hearing in Drosophila. Nature 424:8184[CrossRef][Medline]
- Szallasi A, Blumberg PM 1999 Vanilloid (capsaicin) receptors and mechanisms. Pharmacol Rev 51:159212[Abstract/Free Full Text]
- Howlett AC, Mukhopadhyay S 2000 Cellular signal transduction by anandamide and 2-arachidonoylglycerol. Chem Phys Lipids 108:5370[CrossRef][Medline]
- Elphick MR, Egertova M 2001 The neurobiology and evolution of cannabinoid signalling. Philos Trans R Soc Lond B Biol Sci 356:381408[CrossRef][Medline]
- Laudet V 1997 Evolution of the nuclear receptor superfamily: early diversification from an ancestral orphan receptor. J Mol Endocrinol 19:207226[Abstract/Free Full Text]
- Zhu Y, Rice CD, Pang Y, Pace M, Thomas P 2003 Cloning, expression, and characterization of a membrane progestin receptor and evidence it is an intermediary in meiotic maturation of fish oocytes. Proc Natl Acad Sci USA 100:22312236[Abstract/Free Full Text]
- Zhu Y, Bond J, Thomas P 2003 Identification, classification, and partial characterization of genes in humans and other vertebrates homologous to a fish membrane progestin receptor. Proc Natl Acad Sci USA 100:22372242[Abstract/Free Full Text]
- Oz M, Zhang L, Spivak CE 2002 Direct noncompetitive inhibition of 5-HT(3) receptor-mediated responses by forskolin and steroids. Arch Biochem Biophys 404:293301[CrossRef][Medline]
- Wetzel CH, Hermann B, Behl C, Pestel E, Rammes G, Zieglgansberger W, Holsboer F, Rupprecht R 1998 Functional antagonism of gonadal steroids at the 5-hydroxytryptamine type 3 receptor. Mol Endocrinol 12:14411451[Abstract/Free Full Text]
- Valera S, Ballivet M, Bertrand D 1992 Progesterone modulates a neuronal nicotinic acetylcholine receptor. Proc Natl Acad Sci USA 89:99499953[Abstract/Free Full Text]
- Wang ZY, Seto H, Fujioka S, Yoshida S, Chory J 2001 BRI1 is a critical component of a plasma-membrane receptor for plant steroids. Nature 410:380383[CrossRef][Medline]
- Cano-Delgado A, Yin Y, Yu C, Vafeados D, Mora-Garcia S, Cheng JC, Nam KH, Li J, Chory J 2004 BRL1 and BRL3 are novel brassinosteroid receptors that function in vascular differentiation in Arabidopsis. Development 131:53415351[Abstract/Free Full Text]
- Kim Y, Bang H, Gnatenco C, Kim D 2001 Synergistic interaction and the role of C-terminus in the activation of TRAAK K+ channels by pressure, free fatty acids and alkali. Pflugers Arch 442:6472[CrossRef][Medline]
- Brandt JM, Djouadi F, Kelly DP 1998 Fatty acids activate transcription of the muscle carnitine palmitoyltransferase I gene in cardiac myocytes via the peroxisome proliferator-activated receptor
. J Biol Chem 273:2378623792[Abstract/Free Full Text]
- Itoh Y, Kawamata Y, Harada M, Kobayashi M, Fujii R, Fukusumi S, Ogi K, Hosoya M, Tanaka Y, Uejima H, Tanaka H, Maruyama M, Satoh R, Okubo S, Kizawa H, Komatsu H, Matsumura F, Noguchi Y, Shinohara T, Hinuma S, Fujisawa Y, Fujino M 2003 Free fatty acids regulate insulin secretion from pancreatic ß cells through GPR40. Nature 422:173176[CrossRef][Medline]
- Bonen A, Luiken JJ, Glatz JF 2002 Regulation of fatty acid transport and membrane transporters in health and disease. Mol Cell Biochem 239:181192[CrossRef][Medline]
- Chun J, Goetzl EJ, Hla T, Igarashi Y, Lynch KR, Moolenaar W, Pyne S, Tigyi G 2002 International Union of Pharmacology. XXXIV. Lysophospholipid receptor nomenclature. Pharmacol Rev 54:265269[Abstract/Free Full Text]
- Zhang C, Baker DL, Yasuda S, Makarova N, Balazs L, Johnson LR, Marathe GK, McIntyre TM, Xu Y, Prestwich GD, Byun HS, Bittman R, Tigyi G 2004 Lysophosphatidic acid induces neointima formation through PPAR
activation. J Exp Med 199:763774[Abstract/Free Full Text]
- Gobeil Jr F, Bernier SG, Vazquez-Tello A, Brault S, Beauchamp MH, Quiniou C, Marrache AM, Checchin D, Sennlaub F, Hou X, Nader M, Bkaily G, Ribeiro-da-Silva A, Goetzl EJ, Chemtob S 2003 Modulation of pro-inflammatory gene expression by nuclear lysophosphatidic acid receptor type-1. J Biol Chem 278:3887538883[Abstract/Free Full Text]
- Boie Y, Sawyer N, Slipetz DM, Metters KM, Abramovitz M 1995 Molecular cloning and characterization of the human prostanoid DP receptor. J Biol Chem 270:1891018916[Abstract/Free Full Text]
- Yu K, Bayona W, Kallen CB, Harding HP, Ravera CP, McMahon G, Brown M, Lazar MA 1995 Differential activation of peroxisome proliferator-activated receptors by eicosanoids. J Biol Chem 270:2397523983[Abstract/Free Full Text]
- Banu SK, Arosh JA, Chapdelaine P, Fortier MA 2003 Molecular cloning and spatio-temporal expression of the prostaglandin transporter: a basis for the action of prostaglandins in the bovine reproductive system. Proc Natl Acad Sci USA 100:1174711752[Abstract/Free Full Text]
- Gudermann T, Hofmann T, Mederos Y, Schnitzler M, Dietrich A 2004 Activation, subunit composition and physiological relevance of DAG-sensitive TRPC proteins. Novartis Found Symp 258:103118; discussion 118122, 155159:263266[Medline]
- Maingret F, Patel AJ, Lesage F, Lazdunski M, Honore E 2000 Lysophospholipids open the two-pore domain mechano-gated K(+) channels TREK-1 and TRAAK. J Biol Chem 275:1012810133[Abstract/Free Full Text]
- Kostenis E 2004 A glance at G-protein-coupled receptors for lipid mediators: a growing receptor family with remarkably diverse ligands. Pharmacol Ther 102:243257[CrossRef][Medline]
- Dorsky RI, Moon RT, Raible DW 1998 Control of neural crest cell fate by the Wnt signalling pathway. Nature 396:370373[CrossRef][Medline]
- Auerbach A 2003 Life at the top: the transition state of AChR gating. Sci STKE 2003:re11
- Lu ZL, Saldanha JW, Hulme EC 2001 Transmembrane domains 4 and 7 of the M(1) muscarinic acetylcholine receptor are critical for ligand binding and the receptor activation switch. J Biol Chem 276:3409834104[Abstract/Free Full Text]
- Whiting PJ, Bonnert TP, McKernan RM, Farrar S, Le Bourdelles B, Heavens RP, Smith DW, Hewson L, Rigby MR, Sirinathsinghji DJ, Thompson SA, Wafford KA 1999 Molecular and functional diversity of the expanding GABA-A receptor gene family. Ann NY Acad Sci 868:645653[Abstract/Free Full Text]
- Smith GB, Olsen RW 1995 Functional domains of GABAA receptors. Trends Pharmacol Sci 16:162168[CrossRef][Medline]
- Calver AR, Davies CH, Pangalos M 2002 GABA(B) receptors: from monogamy to promiscuity. Neurosignals 11:299314[CrossRef][Medline]
- Hermans E, Challiss RA 2001 Structural, signalling and regulatory properties of the group I metabotropic glutamate receptors: prototypic family C G-protein-coupled receptors. Biochem J 359:465484[CrossRef][Medline]
- Hampson DR, Huang XP, Pekhletski R, Peltekova V, Hornby G, Thomsen C, Thogersen H 1999 Probing the ligand-binding domain of the mGluR4 subtype of metabotropic glutamate receptor. J Biol Chem 274:3348833495[Abstract/Free Full Text]
- Seal RP, Shigeri Y, Eliasof S, Leighton BH, Amara SG 2001 Sulfhydryl modification of V449C in the glutamate transporter EAAT1 abolishes substrate transport but not the substrate-gated anion conductance. Proc Natl Acad Sci USA 98:1532415329[Abstract/Free Full Text]
- Xia Z, Gray JA, Compton-Toth BA, Roth BL 2003 A direct interaction of PSD-95 with 5-HT2A serotonin receptors regulates receptor trafficking and signal transduction. J Biol Chem 278:2190121908[Abstract/Free Full Text]
- Ralevic V, Kendall DA, Randall MD, Smart D 2002 Cannabinoid modulation of sensory neurotransmission via cannabinoid and vanilloid receptors: roles in regulation of cardiovascular function. Life Sci 71:25772594[CrossRef][Medline]
- Howlett AC, Barth F, Bonner TI, Cabral G, Casellas P, Devane WA, Felder CC, Herkenham M, Mackie K, Martin BR, Mechoulam R, Pertwee RG 2002 International Union of Pharmacology. XXVII. Classification of cannabinoid receptors. Pharmacol Rev 54:161202[Abstract/Free Full Text]
- Gerdes D, Wehling M, Leube B, Falkenstein E 1998 Cloning and tissue expression of two putative steroid membrane receptors. Biol Chem 379:907911[Medline]
- Baker ME 2002 Recent insights into the origins of adrenal and sex steroid receptors. J Mol Endocrinol 28:149152[Abstract/Free Full Text]
- Funk CD 2001 Prostaglandins and leukotrienes: advances in eicosanoid biology. Science 294:18711875[Abstract/Free Full Text]
- Yang L, Andrews DA, Low PS 2000 Lysophosphatidic acid opens a Ca(++) channel in human erythrocytes. Blood 95:24202425[Abstract/Free Full Text]
- Shida D, Kitayama J, Yamaguchi H, Okaji Y, Tsuno NH, Watanabe T, Takuwa Y, Nagawa H 2003 Lysophosphatidic acid (LPA) enhances the metastatic potential of human colon carcinoma DLD1 cells through LPA1. Cancer Res 63:17061711[Abstract/Free Full Text]
- McIntyre TM, Pontsler AV, Silva AR, St Hilaire A, Xu Y, Hinshaw JC, Zimmerman GA, Hama K, Aoki J, Arai H, Prestwich GD 2003 Identification of an intracellular receptor for lysophosphatidic acid (LPA): LPA is a transcellular PPAR
agonist. Proc Natl Acad Sci USA 100:131136[Abstract/Free Full Text]
- Sano Y, Inamura K, Miyake A, Mochizuki S, Kitada C, Yokoi H, Nozawa K, Okada H, Matsushime H, Furuichi K 2003 A novel two-pore domain K+ channel, TRESK, is localized in the spinal cord. J Biol Chem 278: 2740627412