Modulation of cyclic-nucleotide-gated channels and regulation of vertebrate phototransduction
Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720, USA
*e-mail: rhkramer{at}uclink4.berkeley.edu
Accepted June 25, 2001
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Summary |
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Key words: cyclic-nucleotide-gated channel, modulation, phosphorylation, proteinprotein interaction, insulin-like growth factor I, calmodulin, photoreceptor, sensory transduction.
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Cyclic-nucleotide-gated channels and phototransduction |
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The molecular steps of rod phototransduction are well understood (Fig.1). Single photons induce isomerization of rhodopsin, leading to activation of the G-protein transducin and of phosphodiesterase, which hydrolyzes cyclic GMP (cGMP). This leads to a decrease in the cytoplasmic concentration of cGMP and closure of cyclic-nucleotide-gated (CNG) channels. The resulting decrease in the steady inward dark current hyperpolarizes the membrane potential, ultimately leading to a decrease in the tonic release of the neurotransmitter glutamate from the presynaptic terminals.
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Our understanding of photoreceptor CNG channel gating and modulation has been greatly helped by structural and functional comparisons with closely homologous CNG channels from olfactory receptor neurons. The vertebrate olfaction signaling cascade involves odorants binding to G-protein-coupled receptors, activation of adenylate cyclase and synthesis of cyclic AMP, leading to activation of olfactory CNG channels and depolarization of the membrane potential. Like rod CNG channels, olfactory CNG channels are voltage-insensitive, non-selective in their permeability to monovalent cations and do not desensitize with prolonged exposure to ligand. However, olfactory CNG channels have a larger-diameter pore and can be fully activated by either cyclic AMP or cyclic GMP (Dhallan et al., 1990; Goulding et al., 1992). Analysis of chimeric CNG channels, formed by substituting segments of rod with olfactory CNG channels, has elucidated crucial segments, and in some cases individual amino acids, that mediate the effects of modulators on CNG channel gating (Table1).
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Modulation of CNG channels by Ca2+/calmodulin |
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In addition to these effects, Ca2+, in conjunction with calmodulin in rods (Hsu and Molday, 1993) or other Ca2+-binding proteins in cones (Rebrik and Korenbrot, 1998), directly binds to and inhibits CNG channels by reducing their sensitivity to cGMP. In rods, Ca2+/calmodulin binds to the ß-subunit of the rod CNG channel protein (Chen et al., 1994; Hsu and Molday, 1993; Weitz et al., 1998; Grunwald et al., 1998). The binding of Ca2+/calmodulin to CNG channels can alter the interaction between the N and C termini of channel subunits, which may be important for gating (Varnum and Zagotta, 1997). According to this scenario, the drop in intracellular Ca2+ concentration during the light response should favor the reopening of CNG channels, thus extending the operating range of the rod light response. However, the shift in cGMP sensitivity is rather small (two- to threefold) compared with the large change in rod light sensitivity during light adaptation (100- to 1000-fold), suggesting that this mechanism makes only a minor contribution to adaptation in rods (Koutalos and Yau, 1996), although it makes a larger contribution to adaptation in cones (Rebrik and Korenbrot, 1998).
It should be noted that Ca2+/calmodulin also modulates CNG channels in olfactory neurons, but here the binding site is on the -subunit rather than other subunits of the channel (Liu et al., 1994). Like the rod CNG channel, the cyclic-nucleotide-sensitivity (to both cGMP and cAMP) of olfactory CNG channels is reduced by Ca2+ (Kramer and Siegelbaum, 1992). Odorant responses are mediated by an increase in cyclic AMP concentration, which opens CNG channels, depolarizing the cell and allowing Ca2+ influx. The increased Ca2+ influx, followed by inhibition of CNG channels by Ca2+/calmodulin, constitutes a negative feedback system that plays a crucial role in olfactory adaptation in these cells (Kurahashi and Menini, 1997).
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Regulation by nitric oxide |
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Modulation by transition metals |
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Regulation by lipid metabolites |
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Regulation of CNG channels by phosphorylation |
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Studies suggest that CNG channels can be modulated by changes in phosphorylation state catalyzed by serine/threonine protein kinases and phosphatases (Gordon et al., 1992) and, more recently, by protein tyrosine kinases (PTKs) and phosphatases (PTPs) (Molokanova et al., 1997). Two approaches have been used to investigate modulation by changes in phosphorylation state. First, researchers have studied changes in activity brought about by unidentified kinases or phosphatases endogenous to cells expressing the channels (either photoreceptors or exogenous expression systems) (Gordon et al., 1992; Molokanova et al., 1997). The involvement of these enzymes has been deduced from the use of specific kinase or phosphatase inhibitors. In the second approach, defined kinases or phosphatases are applied directly to CNG channels in a cell-free system (usually an excised inside-out membrane patch) (Muller et al., 1998). Unfortunately, kinases and phosphatases are often quite promiscuous: proteins that are not natural physiological targets may nonetheless still be substrates for the enzymes in a cell-free system. Therefore, conclusions about modulation based solely on exogenous enzyme application should be made with caution.
Rod CNG channels formed by expressing the bovine rod -subunit gene in Xenopus laevis oocytes exhibit a particularly clear type of modulation, attributable to changes in tyrosine phosphorylation state (Molokanova et al., 1997; Molokanova et al., 1999a). The key observation is a spontaneous two- to threefold increase in channel cGMP sensitivity, such that CNG currents activated by sub-saturating, but not saturating, cGMP concentrations increase after patch excision (Fig.3A). On average, the K1/2 for activation by cGMP shifts from approximately 120µmoll-1 to approximately 60µmoll-1 within 10min of patch excision (Fig.3B). Addition of ATP to the superfusate partly reverses the effect, but the sensitivity once again begins to increase when ATP is removed. ATP-
-S, which can often support irreversible thio-phosphorylation of proteins, elicits an irreversible effect on cGMP sensitivity. Non-hydrolysable ATP analogs, such as AMP-PNP, which cannot act as substrates in phosphorylation reactions, have no effect. The simplest interpretation of these results is that a protein phosphatase, which dephosphorylates the channel, increases the cGMP sensitivity, while a protein kinase, which phosphorylates the channels in the presence of ATP, makes the channels less sensitive to cGMP. Since the effects occur spontaneously in excised patches, the putative kinases and phosphatases must be constitutively active. Native CNG channels in rod photoreceptors are modulated in a similar manner but, in the absence of Ca2+, an external transmitter is required to trigger changes in phosphorylation state (see below).
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Activity-dependence of modulation by tyrosine phosphorylation |
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Regulation by proteinprotein interactions |
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We have obtained indirect evidence that the rod CNG channel is stably associated with PTK(s). Moreover, at least under some circumstances, the PTK(s) can alter channel function, even in the absence of ATP. Thus, PTKs can modulate CNG channels in two ways: first, by catalyzing phosphorylation and, second, through a non-catalytic allosteric effect that inhibits CNG channel gating.
The non-catalytic inhibition mediated by PTKs can be elicited by applying genistein, a PTK inhibitor that specifically interacts with the ATP-binding site on the enzyme (Molokanova et al., 1999b). Application of genistein dramatically slows the gating of the rod CNG channels and reduces the steady-state current activated by cGMP. Various results, including the observation that agents specific for PTKs prevent genistein inhibition, suggest that genistein inhibition is not mediated by a direct interaction between genistein and the CNG channel, but rather involves an indirect effect mediated by a PTK. The affinity and efficacy of genistein are much higher for closed than for open channels, following the same activity-dependent pattern of phosphorylation of CNG channels by PTKs. These results and others strongly suggest that genistein inhibition involves genistein binding to the PTK which, through an allosteric interaction with the channel, hinders channel gating (Molokanova and Kramer, 2001).
The effect of genistein is not limited to rod CNG channels expressed in oocytes, but also applies to native CNG channels in rods and cones and, to a lesser extent, to olfactory neurons (Molokanova et al., 2000). Moreover, the same criteria used to suggest that genistein acts indirectly (through a PTK) also apply to inhibition of the native channels. It is unclear whether CNG channels and PTK have an intimate or just a casual relationship with one another. Thus, we do not know whether the PTK responsible for genistein inhibition is part of a stable complex with the CNG channel or whether it normally dissociates and reassociates with the channel. Additional biochemical experiments are needed to identify the PTKs that regulate CNG channels and to understand the nature of their relationship.
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Modulation by neurotransmitters |
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Few types of receptors for extrinsic signaling molecules have been found in the plasma membrane of rod outer segments. Those that occur include dopamine receptors (Udovichenko et al., 1998), adenosine A2 receptors (McIntosh and Blazynski, 1994) and receptors for insulin-like growth factor I (IGF-I) (Waldbillig et al., 1991). IGF-I is particularly interesting because it is synthesized and released from retinal pigment epithelial cells (Waldbillig et al., 1991), which lie immediately adjacent to rod outer segments. Moreover, IGF-binding proteins, which may participate in the delivery of IGF-I to receptors, are concentrated in the interphotoreceptor matrix, situated between the RPE and the plasma membrane of outer segments. The RPE plays several crucial roles in supporting photoreceptors, including providing the photopigment 11-cis retinal to rod and cone outer segments and regulating the shedding of discs and from the apical end of outer segments and secretion of several growth factors important for photoreceptor development and long-term survival (Bok, 1993). The finding that one of the growth factors released by the RPE (IGF-I) also acutely regulates the light response (Savchenko et al., 2001) suggests that the RPE also has a more dynamic neuromodulatory function.
Application of IGF-I to rod outer segments leads to a two- to threefold increase in the sensitivity of CNG channels to cGMP (Savchenko et al., 2001) (Fig.5A,B). The effect of IGF-I occurs within tens of seconds and dissipates with equal rapidity after removal of IGF-I. Various lines of evidence suggest that the effect of IGF-I involves a complex signaling pathway, ending with tyrosine dephosphorylation of the rod CNG channel. Parallel experiments performed on rod CNG channel -subunits expressed in Xenopus laevis oocytes, which have their own IGF-I receptors, show that IGF-I also increases the cGMP sensitivity of the channels, but only if the crucial tyrosine (Y498) is present. Hence, when this tyrosine is substituted with a phenylalanine (mutant Y498F), the channels are unaffected when the oocyte is exposed to IGF-I. These results suggest that the effect of IGF-I not only involves tyrosine dephosphorylation but that the crucial target is the same specific tyrosine residue implicated in spontaneous modulation in oocytes.
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It is possible that IGF-I plays a role in slow forms of light adaptation in rods. Rapidly decaying photoreceptor adaptation, lasting seconds to minutes, is intrinsic to rods and cones and can be attributed entirely to modulation of the phototransduction cascade by light-driven changes in intracellular Ca2+ concentration (for a review, see Pugh et al., 1999). A much more slowly recovering change in responsiveness, lasting minutes to hours, termed photochemical adaptation, requires the RPE and has been attributed to regeneration of bleached photopigment (Dowling, 1987). In addition to this type of slow adaptation, which is only apparent at high light intensities sufficient to bleach most of the rhodopsin, there are more subtle changes in light sensitivity in response to hormones or associated with free-running circadian rhythms (see below). In addition, slow light-driven diurnal changes have been reported (Schaeffel et al., 1991; Birch et al., 1994). The modest effects elicited by IGF-I are more likely to be involved in these more subtle slow changes in light sensitivity.
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Circadian regulation of CNG channels |
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Concluding remarks |
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Acknowledgments |
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