Neuromodulators and Signaling Cascades in Retina

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DESCRIPTION (provided by applicant): Photoreceptor cells are the primary sensory neurons of the visual system. In addition to being regulated by light, aspects of photoreceptor physiology are subject to control by neuromodulators, such as dopamine, adenosine, somatostatin, and nitric oxide. Much of the data supporting a role for these substances in photoreceptor cell function is pharmacological in nature, obtained from non-mammalian vertebrates, and much remains to be learned about the signaling mechanisms involved. Our preliminary data in mouse led to the hypothesis that dopamine, acting on dopamine D4 receptors, plays a major role in regulating cAMP metabolism in photoreceptor cells by Ca 2+ -dependent regulation of adenylyl cyclase and by regulating gene expression for components of the signaling cascade that links light exposure to inhibition of cAMP formation. Preliminary data also show that dopamine plays a major role in adaptive responses of mouse retina to changing illumination, possibly through a cAMP-dependent mechanism. The present goal is to test these hypotheses and to thereby elucidate the signaling mechanisms whereby dopamine produces it's effects on photoreceptor gene expression and retinal function during light- and dark-adaptation. Using mouse retina as an experimental model, we will test the following predictions of hypotheses: (1) Dopamine D4 receptors on photoreceptor cells regulate gene expression of one or more components of the signaling pathway that couples light-exposure to suppression of cAMP synthesis. (2) Dysfunctional cAMP regulation in photoreceptors of dopamine D4 receptor deficient mice alters photoreceptor gene expression profiles and posttranslational modification of key gene products, such as phosducin. (3) Dopamine and light decrease photoreceptor cAMP levels by reducing the activity of Ca 2+ / calmodutin-stimulated adenylyl cyclases. (4) Decreased expression of Ca 2+ / calmodulin-stimulated adenylyl cyclase(s) leads to the abnormalities of light and dark adaptation seen in dopamine D4 receptor deficient mice. The results of these experiments will significantly enhance our understanding of how dopamine and cAMP modulate photoreceptor function, especially light- and dark-adaptation.