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Inhibition of Retinal Guanylyl Cyclase by the RGS9-1 N-Terminus

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Abstract

Cyclic GMP plays a key role in retinal phototransduction and its photoreceptor concentration is precisely controlled by the cooperative action of cGMP phosphodiesterase (PDE) and retinal guanylyl cyclase (retGC). However, studies of the relationship between these two systems have focused only on a Ca2+-mediated, indirect connection. Using a retinal “regulator of G-protein signaling” (RGS9-1) and its fragments, we show that the N-terminus of RGS9-1 inhibits retGC activity. We also indicate that the GGL domain and/or the RGS domain function as an internal suppressor against the N-terminus, suggesting that proteins bound to these domains regulate the inhibitory activity of the N-terminus. Direct interaction of retGC with RGS9-1 and its N-terminus is also proved by immunoprecipitation and an overlay technique. Since RGS9-1 also controls the lifetime of transducin-activated PDE through regulating GTPase activity of transducin, this study strongly suggests that RGS9-1 mediates the direct interaction between PDE and retGC systems, and that this ingenious mechanism plays an important role in tuning of cGMP concentration in photoreceptors.

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    This work was supported by a National Institutes of Health Grant EY09631 and an unrestricted grant from Research to Prevent Blindness.

    1

    To whom correspondence should be addressed at Kresge Eye Institute, Wayne State University, School of Medicine, 4717 St. Antoine Street, Detroit, MI 48201. Fax: 313-577-0238. E-mail: [email protected].

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