Inhibition of retinal guanylyl cyclase by the RGS9-1 N-terminus

Cyclic GMP plays a key role in retinal phototransduction and its photorecep tor concentration is precisely controlled by the cooperative action of cGMP phosphodiesterase (PDE) and retinal guanylyl cyclase (retGC). However, stu dies of the relationship between these two systems have focused only on a C a2+-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, sugge sting that proteins bound to these domains regulate the inhibitory activity of the N-terminus. Direct interaction of retGC with RGS9-1 and its N-termi nus is also proved by immunoprecipitation and an overlay technique. Since R GS9-1 also controls the lifetime of transducin-activated PDE through regula ting GTPase activity of transducin, this study strongly suggests that RGS9- 1 mediates the direct interaction between PDE and retGC systems, and that t his ingenious mechanism plays an important role in tuning of cGMP concentra tion in photoreceptors. (C) 2001 Academic Press.