Actualité moléculaire de la phototransduction des bâtonnets rétiniens.

Abstract

Dans les bâtonnets rétiniens, quatre protéines pourraient suffire à la production d'un signal cellulaire à partir de la photo-isomérisation d'un rétinal. La rhodopsine active de nombreuses sous-unités de la transducine qui activent à leur tour la phosphodiestérase du GMPc. Une chute brutale et massive de ce dernier entraîne la fermeture des canaux ioniques dans la membrane cellulaire, et la production du signal d'hyperpolarisation. Mais la mise en forme du signal, son adaptation et sa terminaison très rapide demandent un réglage extrêmement subtil. Il est effectué pour une grande part par des calciprotéines sensibles à la chute du calcium qui suit la fermeture des canaux dépendants du GMP cyclique. Au total, une vingtaine de sous-unités protéiques ont été identifiées, qui participent directement à la transmission du signal dans les segments externes des bâtonnets, et suffisent à rendre compte de la plupart des caractéristiques, cinétiques et adaptatives, des réponses physiologiques. Des mutations sur tous les gènes correspondants sont susceptibles d'induire des maladies très diverses, fonctionnelles et/ou dégénératives.

In retinal rod outer segments, four proteins could suffice to transduce the molecular trigger of retinal photoisomerisation into the cellular hyperpolarisation signal: a photoactivated rhodopsine (Rh*) activates many T< alpha > subunits of transducin, an heterotrimeric G-protein which in turn activates a cGMP specific phosphodiesterase (PDE). The drop in cGMP induces the closure of cGMP sensitive cationic channel proteins in the cell membrane, hence the generation of the hyperpolarising signal. But pulse shaping, adaptation and rapid termination of the signal require subtle regulations. Most of them are based on retroaction of calcium sensing calciproteins which detect the drop in calcium subsequent to the closure of the cGMP-sensitive sensitive channels. Three proteins at least regulates Rh* activity: rhodopsine kinase, itself regulated by the calciprotein recoverin, and arrestin, which has at least two fast and slow variants. The activity of transducin T< alpha >GTP subunit on PDE is regulated mainly by a recently identified GTPase activating protein, RGS9, whose action is modulated by the PDE< gamma > subunit of PDE. Furthermore recycling of T< alpha >GDP is regulated by phosducin which can sequester T< beta >< gamma > subunits hence inhibiting regeneration of T< alpha >GDP-T< beta >< gamma >. cGMP levels are regulated by a guanylate cyclase, the activity of which is modulated by the calciprotein GCAP1. Finally the cGMP sensitive channels cationic conductance is modulated by calmoduline and possibly still another calciprotein. Altogether about 20 protein subunits have been identified that participate directly to the transduction of the signal in the rod outer segment, and may account for most of the kinetic and adaptation characteristics of the physiological response. Mutations on all the corresponding genes may induce functional and/or degenerative retinal pathologies.