Molecular Mechanisms for Phosphoinositide Regulation of Cone Photoreceptor Cng Channel Gating
نویسندگان
چکیده
By Gucan Dai, Ph.D. Washington State University May, 2014 Chair: Michael D. Varnum Photoreceptor cyclic nucleotide-gated (CNG) channels are critical for converting light inputs into electrical signals that are ultimately processed as visual information. However, it is not well understood how exactly photoreceptor CNG channels are regulated. Since the first study showing the direct activation of inward rectifier K channels by phosphoinositides in 1998 (Huang et al., 1998), emerging evidences have revealed that phosphoinositides (PIPn), which are low-abundance membrane-bound phospholipids, have tremendous effects on membrane ion channels. Previous studies on rod, cone and olfactory CNG channels have shown that the activities of CNG channels are inhibited by phosphoinositides [phosphatidylinositol 4,5-biphosphate (PIP2) and phosphatidylinositol 3,4,5-triphosphate (PIP3)], exhibiting a decrease in apparent cGMP affinity. Using electrophysiology combined with biochemistry and molecular manipulations, we have investigated the structural elements that are critical for PIP2 and PIP3 regulation of cone CNG channels. We have discovered two phosphoinositideregulation sites within the amino (N) -terminal and the carboxyl (C) -terminal regions of CNGA3 subunits, respectively; CNGB3 subunits do not contain PIPn-sensitive elements. Both of these two phosphoinositide-regulation modules are necessary for PIPn-
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