The Interactive Fly
Zygotically transcribed genes
Drosophila visual signal transduction, the process by which incoming light is converted to neural signals that can be passed to the brain, provides an ideal system for the molecular dissection the process by which extracellular signals are transduced across the plasma membrane leading to neuron activation. In this signal transduction pathway, light stimulates rhodopsin, which activates an eye-specific G protein (Galphaq). Six genes have been identified that code for different Rhodopsins expressed in different sets of photoreceptor cells in the visual system (FlyBase, 1998). The phototransduction cascade is one of the fastest known G protein receptor coupling systems. In Drosophila, the high temporal resolution is evidenced by the less than 20 milli-second latency between photon excitation and photoreceptor cell depolarization (Ranganathan, 1991). Activated Galphaq triggers NorpA (no receptor potential A), a phospholipase C-beta to catalyze the breakdown of phospholipids to generate inositol trisphosphate (IP3) and diacylglycerol. Both Trp (transient receptor potential) and Trp-like are cation channels that are activated in the visual transduction process. These two proteins share homology with alpha-subunits of voltage-gated calcium and sodium channels in vertebrates. The rise in IP3 is thought to result in the release of Ca2+ from the internal Ca2+ stores. However, the release of Ca2+ has been shown not to involved the Inositol 1,4,5,-tris-phosphate receptor, leaving unanswered questions as to the source and regulation of the initial Ca2+ current (Acharya, 1997). It has now been shown, however, that polyunsaturated fatty acids activate the Drosophila light-sensitive channels TRP and TRPL. As arachidonic acid may not be found in Drosophila, it is suggested that another polyunsaturated fatty acid, such as linolenic acid, may be a messenger of excitation in Drosophila photoreceptors (Chyb, 1999). The opening of Ca2+ channels leads to depolarization of photoreceptors. This depolarization leads to the activation of the the Trp store-operated Ca2+ channel. The store-operated calcium channel in the plasma membrane is responsible for replenishing the internal calcium stores depleted during phosphoinositide-mediated process (Shieh, 1997 and references).
Among the proteins of critical importance in visual phototransduction is Inactivation-no-afterpotential D, a photoreceptor-specific protein containing five repeated protein interaction motifs known as PDZ repeats. InaD is an adaptor protein that homomultimultimerizes and has the ability to interacts with multiple components of the signal transduction pathway, including Rhodopsin, NorpA, PKC, Calmodulin, Trp and Trp-like (Shieh, 1997 and references and Xu, 1998a and references). The view that signaling through G protein-coupled cascades occurs via random stochastic collisions between membrane receptors and effector molecules has been widely held for many years. However, the alternative proposal suggesting that signaling cascades are comprised of components that are physically coupled seems to better reflect reality. Work of several research groups have shown that Drosophila vision is mediated by a massive supramolecular complex and that assembly of such a complex is facilitated by homomultimerization of the scaffold protein InaD. Thus, most of the proteins critical in phototransduction appear to couple directly to InaD. The InaD supramolecular complex may not be a particle, consisting of a single InaD monomer to which a maximum of five target proteins bind. Instead, the visual cascade appears to be mediated through a more complicated higher order signaling web or complex (signalplex) consisting of an extended network of InaD homomultimers to which more than five targets bind. Most of these targets appear to bind to more than one PDZ module and several targets appear to associate with INAD via the same PDZ domains. Thus, the nature of the InaD signalplex appears to be more complicated than a single particle held together by a scaffolding protein (Xu, 1998a and references).
An important Ca2+ sensor in Drosophila vision appears to be Calmodulin, since a reduction in levels of retinal Calmodulin causes defects in adaptation and termination of the photoresponse. These functions of Calmodulin appear to be mediated, at least in part, by four calmodulin-binding proteins: the Trp and Trp-like ion channels, NinaC and InaD. Eight additional Calmodulin-binding proteins have been found to be expressed in the Drosophila retina. These included six targets that were related to proteins implicated in synaptic transmission. Among these six are a homolog of the diacylglycerol-binding protein, UNC13, and a protein, CRAG, related to Rab3 GTPase exchange proteins. Both UNC13 and CRAG are implicated in the regulation of synaptic vesicle exocytosis. Two other calmodulin-binding proteins included Pollux, a protein with similarity to a portion of a yeast Rab GTPase activating protein, and Calossin, an enormous protein of unknown function conserved throughout animal phylogeny. The full-length sequences corresponding to three of the calmodulin-binding proteins have been described previously. These corresponded to two Calmodulin-dependent protein kinases, MLCK and CaM kinase II, as well as to one of the two previously described Calcineurin proteins. A third calmodulin-dependent protein kinase is expressed in the Drosophila retina, CaM kinase I. No CaM kinase I had previously been reported from any invertebrate raising the possibility that this protein kinase was specific to vertebrates. Nevertheless, the Drosophila CaM kinase I was highly related, ~60% identical over 349 amino acids, to vertebrate CaM kinase I. Thus, it appears that calmodulin functions as a Ca2+ sensor for a broad diversity of retinal proteins, some of which are implicated in synaptic transmission, and others directly in phototransduction (Xu, 1998b).
References
Acharya, J. K., et al. (1997). InsP3 receptor is essential for growth and differentiation but not for vision in Drosophila. Neuron 18: 881-887
Chyb, S., Raghu, P. and Hardie, R. C. (1999). Polyunsaturated fatty acids activate the Drosophila light-sensitive channels TRP and TRPL. Nature 397(6716): 255-9
Shieh, B. H., Zhu, M. Y., Lee, J. K., Kelly, I. M. and Bahiraei, F. (1997). Association of INAD with NORPA is essential for controlled activation and deactivation of Drosophila phototransduction in vivo. Proc. Natl. Acad. Sci. 94(23): 12682-12687
Xu, X. Z., et al. (1998a). Coordination of an array of signaling proteins through homo- and heteromeric interactions between PDZ domains and target proteins. J. Cell Biol. 142(2): 545-55
date revised: 20 November 2007
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