Phototransduction in Drosophila melanogaster
Cambridge University, Department of Anatomy, Downing Street, Cambridge CB2 3DY, UK
*e-mail: rch14{at}hermes.cam.ac.uk
Accepted July 23, 2001
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Summary |
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Key words: phototransduction, Drosophila melanogaster, phosphoinositide, light-sensitive channel, calcium, inositol trisphosphate, vision, TRP, diacyl glycerol, PIP2, phospholipase C.
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Introduction |
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In all ocular photoreceptors, incident light is absorbed by a membrane-bound visual pigment, rhodopsin, and transduced into conductance changes in the plasma membrane by a G-protein-coupled signalling cascade. Whilst other G-protein-coupled receptors are activated by chemical messengers, rhodopsin is activated by absorption of light by the covalently bound chromophore 11-cis retinal (or, in dipteran flies, 11-cis 3-hydroxy retinal) (Vogt and Kirschfeld, 1984). The resulting photoisomerization to all-trans retinal triggers the conversion of rhodopsin (Rh) to the active metarhodopsin (M) state, which catalyses the activation of a heterotrimeric G-protein. As with all such G-proteins, this involves nucleotide exchange (GTP for GDP) and subsequent dissociation of the G subunit, which remains active until the bound GTP is hydrolysed. In vertebrates, the G-protein (transducin) binds to and activates the effector enzyme, phosphodiesterase (PDE), leading to hydrolysis of cGMP. In contrast, in most invertebrates, the effector enzyme is phosphoinositide-specific phospholipase C (PLCß), which hydrolyses the minor membrane phospholipid phosphatidyl inositol 4,5-bisphosphate (PIP2) to produce soluble inositol 1,4,5-trisphosphate (InsP3) and diacylglycerol (DAG) (Fig. 1). By an as yet unknown mechanism, which very likely differs in different invertebrates, this results in the activation of cation-permeable channels and membrane depolarisation. More generally, the phosphoinositide cascade is of central importance in controlling cellular Ca2+ levels, both by releasing Ca2+ from InsP3-sensitive stores and by activating Ca2+ influx through specific channels in the plasma membrane, often via so-called store-operated Ca2+ channels which are activated by the reduction of levels of Ca2+ in the store lumen (Berridge et al., 2000). The central role of PLC in invertebrate photoreceptors is not disputed, but how activation of PLC is linked to opening of the light-sensitive channels remains one of the major unresolved questions in sensory transduction.
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The light-sensitive channels: TRP and TRPL |
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TRP is the defining member of a novel family of ion channels, with approximately 20 mammalian isoforms divided into several subfamilies [for a review, see (Harteneck et al., 2000; Clapham et al., 2001)]. Isoforms most closely related to Drosophila melanogaster trp and trpl form a distinct subfamily (TRPC1TRPC7), all of which appear to be activated downstream of PLC and possibly include channels responsible for store-operated Ca2+ entry. The more distantly related TRPs include a bewildering variety of channels, such as the vanilloid receptor (VR1 or capsaicin receptor=TRPV1) involved in thermal nociception (Caterina et al., 1997), osmotically activated channels (Strotmann et al., 2000), Ca2+ transporters in gut and kidney (Hoenderop et al., 1999; Peng et al., 1999), mechanosensitive ion channels found in Drosophila melanogaster sensory hairs (Walker et al., 2000) and novel channels of obscure function, such as TRPM7 (=TRP-PLIK) and TRPM2 (=LTRPC2) notable for harbouring enzymatic domains in their C termini (Perraud et al., 2001; Runnels et al., 2001).
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The enigma of excitation |
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Given the requirement for PLC, alternative excitatory signals might include DAG or the reduction in PIP2 levels. The most familiar action of DAG is to activate protein kinase C (PKC) in concert with Ca2+, but mutants of eye PKC have defects only in response inactivation and adaptation, leaving excitation unaffected (Hardie et al., 1993; Smith et al., 1991). However, DAG has other roles, such as a precursor for polyunsaturated fatty acids (PUFAs) via the action of DAG lipase. A recent study showed that both TRP and TRPL channels could be activated by PUFAs downstream of PLC (Chyb et al., 1999). The significance of this result has been questioned since PUFAs can uncouple mitochondria, and ATP depletion has also been shown to activate the light-sensitive channels (Agam et al., 2000). However, this cannot explain the activation of heterologously expressed TRPL channels by PUFAs in excised inside-out patches (Chyb et al., 1999). More recently, Estacion et al. (Estacion et al., 2001) found that heterologously expressed TRPL channels can also be activated by DAG, but reported that some of the actions of both DAG and PUFAs may be indirect via activation of PLC in the excised patches. The activity of TRPL channels in excised patches was suppressed by application of PIP2, suggesting PIP2 depletion as a potential contributory factor to channel gating. This seems unlikely to account for activation of TRPL in vivo since, under conditions in which PIP2 is severely depleted, TRPL channels in the trp mutant become completely inactivated and can be reactivated by light only after PIP2 is resynthesised. Nevertheless, under the same conditions of PIP2 depletion, TRP channels tend to remain constitutively activated, suggesting that PIP2 depletion might reward further attention as a mechanism of activation of TRP (Hardie et al., 2001).
Independent evidence for an excitatory role for DAG comes from the rdgA mutant. The rdgA gene encodes DAG kinase, which inactivates DAG by converting it to phosphatidic acid (Masai et al., 1993). rdgA mutants undergo severe retinal degeneration, and the photoreceptors show no response to light. When investigated with whole-cell voltage-clamp techniques, the TRP channels in rdgA mutants are constitutively active, and it seems that the resultant Ca2+ influx may cause the severe degeneration because this was rescued in rdgA;trp double mutants (Raghu et al., 2000b). The response to light was also rescued in the double mutant, but failed to terminate normally, indicating that DAG kinase is required for response termination. The constitutive activity of the TRP channels and the deactivation defect would be consistent with a role for DAG in excitation. However, DAG kinase is also the first enzymatic step in the resynthesis of PIP2, so that PIP2 levels and the kinetics of PIP2 recycling may also be affected in the rdgA mutant.
In summary, there is little evidence to support a role for InsP3 in phototransduction in Drosophila melanogaster, whilst several recent studies have suggested that alternative actions of PLC (i.e. the production of DAG, PUFAs and/or a reduction in PIP2 levels) may be important. Resolution of the mechanism of excitation might require, inter alia, identification and characterization of ligand-binding sites on the channel molecules, biochemical analysis of light-induced lipid metabolism and molecular identification and mutant analysis of any further gene products required for activation. In this respect, a mutation of a novel protein (INAF) with no known homologues has recently been shown to mimic aspects of the trp phenotype, suggesting that it may be required for TRP activation (Li et al., 1999).
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Response termination |
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Activated rhodopsin is inactivated by binding to arrestin
Drosophila melanogaster photoreceptors actually express two arrestin isoforms, one of which, arr2, appears to play the dominant role in inactivation (Dolph et al., 1993). Rhodopsin is also multiply phosphorylated by rhodopsin kinase, and in vertebrates this is essential for inactivation (Chen et al., 1995). But, in Drosophila melanogaster, flies expressing a truncated rhodopsin construct in which the phosphorylation sites are deleted show no defects in electrical responses or in the ability of arrestin to bind to rhodopsin (Vinos et al., 1997), implying that the phosphorylation plays no direct role in phototransduction.
Activity of both the GTP-bound Gq subunit and PLC is terminated by the GTPase activity of the G-protein
The intrinsic GTPase activity of the G-protein is much too slow to account for the rapid response termination, and it is now clear that, as in rods, the effector enzyme itself (PDE in rods, PLC in flies) acts as a GTPase-activating protein (GAP) to accelerate GTP hydrolysis. This is most clearly seen in norpA hypomorphs with reduced levels of PLC, in which responses can be elicited up to a minute after absorption of light. Presumably, this represents the time taken for individual activated G-proteins to diffuse in the membrane before encountering a rare PLC molecule, in turn demonstrating that Gq remains active until it encounters PLC (Cook et al., 2000; Scott and Zuker, 1998). In vertebrate rods, additional proteins (RGS9=regulator of G-protein signalling and Gß5) are also required for GAP activity of the effector enzyme (Arshavsky and Pugh, 1998). Whether homologous proteins play similar roles in Drosophila melanogaster photoreceptors is not known.
Light-sensitive channels
Both classes of light-sensitive channel are rapidly inactivated by Ca2+, e.g. (Reuss et al., 1997). This may involve calmodulin (CaM), since TRP contains one and TRPL two calmodulin-binding sites (Chevesich et al., 1997; Warr and Kelly, 1996) and light responses in Cam hypomorphs or flies expressing a mutant TRPL construct with one or other calmodulin-binding site deleted show delayed response inactivation (Scott et al., 1997). The TRP channel is also subject to a voltage-dependent Mg2+ block, which intensifies over the physiological range of membrane potentials (70 to 0 mV). This would appear to be an elegant and economic mechanism for gain reduction during light adaptation when the membrane depolarises by some 3040 mV (Hardie and Mojet, 1995).
Protein kinase C
Mutants of the photoreceptor PKC (inaC) have severe defects in response deactivation and light adaptation (Hardie et al., 1993; Smith et al., 1991). At least two PKC phosphorylation targets have been identified, namely the TRP channel and the INAD scaffolding protein (Huber et al., 1998; see further below), although whether either of these is responsible for the inaC deactivation phenotype remains to be seen.
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Quantum bump generation |
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The amplification downstream of PLC and the rapid inactivation of the quantum bump are both dependent upon Ca2+ influx through the light-sensitive channels. Bump amplitude is reduced approximately 10-fold at low external Ca2+ concentrations, whilst bump duration increases dramatically (Henderson et al., 2000). At intermediate external Ca2+ concentrations, bumps develop with a small slow rising phase that abruptly accelerates to yield a full-sized bump (Fig. 2B), suggesting that Ca2+ influx must reach a threshold before triggering a cycle of positive and negative feedback responsible for amplification and rapid inactivation. A plausible mechanism for facilitation would be that Ca2+ increases the affinity of the channel for the putative second messenger, so that the near-threshold concentration of transmitter that builds up during the latent period suddenly becomes saturating.
In mutants of arrestin or calmodulin (which affects arrestin binding indirectly), activated rhodopsin (metarhodopsin) lifetime is greatly prolonged. Bump waveforms are unaffected in such mutants, but each absorbed photon gives rise to multiple trains of bumps separated by 100200 ms (Scott et al., 1997). This indicates that the same rhodopsin molecule can generate a second bump after a brief refractory period. The first evidence for a refractory period came from paired flash experiments in Calliphora vicina showing that the response to a second flash was completely abolished by an adapting flash of intensity just sufficient to ensure that every microvillus had absorbed at least one photon. Complete inactivation was only transient, substantial sensitivity recovering within 50 ms (Hochstrate and Hamdorf, 1990). The refractory period is probably caused by extremely high Ca2+ concentrations that are believed to exceed 200 µmol l1 during the lifetime of the bump (Oberwinkler and Stavenga, 2000; Postma et al., 1999) and might end when the Ca2+ inside the microvilli has been removed by diffusion and/or by the Na+/Ca2+ exchanger [within approximately 100 ms and faster when light-adapted, according to measurements in Calliphora (Oberwinkler and Stavenga, 2000)]. Accordingly, if Na+/Ca2+ exchange is temporarily blocked by removing external Na+, a single flash containing sufficient photons to activate the majority of microvilli renders the photoreceptor refractory to further stimulation until the Na+ is returned to the bath (S. Moore and R. C. Hardie, unpublished data).
Under light-adapted conditions, each quantum bump becomes progressively reduced in amplitude and duration as a result of the negative feedback from the raised steady-state [Ca2+]; nevertheless, noise analysis suggests that the photoreceptors continue acting as linear photon counters up to daylight intensities (Wong, 1982; Howard et al., 1987; Juusola and Hardie, 2001). This can be readily understood if it is assumed that each microvillus is a semi-autonomous unit of excitation and can be recycled for action within 100 ms, or less when light-adapted, thereby allowing the 30 000 microvilli in each Drosophila melanogaster rhabdomere to process in excess of 30 000 photons s1, as observed experimentally (Juusola and Hardie, 2001). After taking into account the approximately 12 log unit attenuation of the incident light flux by the pupil pigment granules, which migrate towards the rhabdomere when light-adapted, this is sufficient to avoid saturation under the brightest daylight intensities (Howard et al., 1987; Juusola and Hardie, 2001).
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The INAD signalling complex |
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Concluding remarks and outlook |
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Acknowledgments |
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