Feedback regulation of cone cyclic nucleotide channels by phosphoinositides. Focus on "CNGA3 achromatopsia-associated mutation potentiates the phosphoinositide sensitivity of cone photoreceptor CNG channels by altering intersubunit interactions".

THE TRANSFORMATION OF LIGHT into electrical signals is the first step in the visual response. The molecular machinery responsible for this transformation is arguably the best understood cellular signaling pathway. In this pathway, light-mediated activation of the G protein-coupled receptor rhodopsin (R) triggers the G protein transducin (T) to exchange GDP for GTP. One activated rhodopsin (R*) can activate hundreds of molecules of transducin; each transducin-GTP complex in turn activates phosphodiesterase type 6 (PDE6). PDE6 hydrolyzes cGMP to 5=-GMP, lowering cGMP to levels that no longer activate cyclic nucleotide-gated (CNG) channels. Closure of CNG channels disrupts the balance of ionic fluxes and hyperpolarizes the plasma membrane, thereby generating an electrical signal. Several feedback mechanisms are critical for rapid shutdown of this signal (2, 4): phosphorylation of R* leads to arrestin binding, receptor desensitization, and thus blocks Rmediated activation of T; RGS9 accelerates the GTPase activity of T, shutting down T-mediated activation of PDE6; and closure of CNG channels lowers intracellular Ca levels and relieves Ca -mediated inhibition of guanylyl cyclase (GC) activity, increasing cGMP production, and a more rapid recovery to baseline cGMP levels. Both signal amplification and feedback regulation are critical in generating reproducible electrical signals in response to changes in light. Feedback regulation also underlies adaptation to dim or bright backgrounds. Ca -mediated feedback is thought to be largely responsible for adaptation and involves several processes: Ca -mediated inhibition of GC activity; Ca -calmodulin-mediated inhibition of CNG channels—a small effect in cones; and, in cones, modulation of CNG channel activity by CNG-modulin (4, 7, 10). The potential roles of other messengers in feedback regulation of the light response are less well understood. Phosphoinositides (PIPs) are one such set of messengers (Fig. 1A). Photoreceptors contain the enzymes necessary for PIP turnover and have increased PIP production and degradation in response to sustained exposure to light (8). PIPs have been implicated both in the enhancement of transducinPDE6 interactions leading to increased PDE6 activity and in the inhibition of cone CNG channels (3, 9). However, the roles of PIPs in regulating light responses have been difficult to discern, in part because of a limited understanding of the molecular mechanisms underlying PIP-mediated feedback and of the changes in PIP levels triggered by variations in background light levels. Recently, M. D. Varnum and colleagues have unraveled the mechanisms by which PIPs alter the cyclic nucleotide sensitivity of cone CNG channels (5, 6). CNG channels are tetramers with four cyclic nucleotide binding sites and a common ion conduction pore. The binding Address for reprint requests and other correspondence: T. C. Rich, Center for Lung Biology, Univ. of South Alabama, Mobile, AL 36688 (e-mail: [email protected]).