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'

摘要

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 hyper-polarizes 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 R-mediated 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~(2+) levels and relieves Ca~(2+)-mediated inhibition of guanylyl cyclase (GC) activity, increasing cGMP production, and a more rapid recovery to baseline cGMP levels. Both signal amplification and