Departments of Biochemistry, Neurosciences and Psychiatry, NIMH Psychoactive Drug Screening Program, Case Western Reserve University, School of Medicine, Cleveland, OH 44106, USA
* Author for correspondence (e-mail: roth{at}biocserver.cwru.edu)
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Introduction |
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The presence of GPCRs in the genomes of bacteria, yeast, plants, nematodes and other invertebrate groups argues in favor of a relatively early evolutionary origin of this group of molecules. The diversity of GPCRs is dictated both by the multiplicity of stimuli to which they respond, as well as by the variety of intracellular signalling pathways they activate. These include light, neurotransmitters, odorants, biogenic amines, lipids, proteins, amino acids, hormones, nucleotides, chemokines and, undoubtedly, many others. In addition, there are at least 18 different human G proteins to which GPCRs can be coupled (Hermans, 2003
; Wong, 2003
). These G
proteins form heterotrimeric complexes with Gß subunits, of which there are at least 5 types, and G
subunits, of which there are at least 11 types (Hermans, 2003
).
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The tree shown illustrates the relationships among the primary protein sequences of 274 type A rhodopsin-like GPCRs; for clarity, the secretin family receptors (of which there are 15), the adhesion receptor family (24), the glutamate receptor family (15) and the frizzled/taste2 receptor family (24) were not included. To construct this tree, the list of receptors used by Fredriksson et al. (Fredriksson et al., 2003) served as a starting point, and newly discovered `orphan' receptors were added to the list (http://kidb.bioc.cwru.edu/rothlab/jalview/viewJalView.html).
The protein sequence of each receptor was obtained, and the sequences of the N- and C-termini, which are of variable length and show little similarity among the receptors, were trimmed manually. The protein sequences were then aligned and the tree was drawn using the ClustalW server (http://clustalw.genome.ad.jp). An alignment file is available at http://kidb.bioc.cwru.edu/rothlab/jalview/viewJalView.html and can be examined with a more viewer-friendly interface using the JalView applet at that site. The G-protein-coupling information in the poster is derived from the review by Wong (Wong, 2003).
The groupings of the receptors in the poster are thus similar, but not identical, to those of Fredriksson et al. (Fredriksson et al., 2003). For example, Fredriksson's
, ß,
and
groups, which appear to be `monophyletic' in their tree, were not monophyletic in ours; this is likely to be due to slight differences in the options used in the two alignments, and the relative imprecision of the location of the roots of the branches in both trees. Interestingly, the orphan receptors GPR57 and GPR58 were grouped with the trace amine receptors, and comparison of their sequences indicates that these orphans probably constitute the human equivalent of the type 2 trace amine receptors of rodents. Thus, trees of this type may serve to help in the process of `de-orphanizing' receptors.
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How do GPCRs work? |
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Although many studies have used ß-adrenergic receptors as prototypical GPCRs, it has become increasingly clear that much more can be learned by systematic study of other receptors. Our studies of the serotonin 5-HT2A receptor, for instance, showed that GPCR internalization and desensitization can occur by arrestin-independent pathways (Bhatnagar et al., 2001; Gray et al., 2003
) and similar findings have been reported for other GPCRs (Lee et al., 1998
). Interactions of GPCRs with other proteins, including cytoskeletal components such as PSD-95 (Hall and Lefkowitz, 2002
; Xia et al., 2003
), are increasingly being found to be important for regulating the activity, targeting and trafficking of GPCRs.
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GPCRs are attractive targets for magic bullets |
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In addition to biological studies of the types summarized above, much excitement remains in the field because of the continuing de-orphanization of GPCRs and the subsequent elucidation of their pharmacology and physiology.
Once a large enough panel of GPCRs has been obtained and comprehensively characterized, a systematic analysis of the `receptorome' (the portion of the proteome encoding receptors) can yield important discoveries. We have used such an approach to discover the molecular mechanisms responsible for serious drug side-effects for example, phen/fen-induced heart disease (Rothman et al., 2000) and weight gain associated with the use of atypical antipsychotics (Kroeze et al., 2003
). Additionally, screening the receptorome has been used to elucidate the actions of natural compounds and to obtain validated molecular targets for drug discovery (e.g. Roth et al., 2002
).
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References |
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