Insulin receptor regulates photoreceptor CNG channel activity

Abstract

Gupta VK, Rajala A, Rajala RV. Insulin receptor regulates photoreceptor cng channel activity. Am J Physiol Endocrinol Metab 303: E1363-E1372, 2012. First published October 2, 2012; doi:10.1152/ajpendo.00199.2012.-Photoreceptor cyclic nucleotide gated (CNG) channels are critical elements in phototransduction and light adaptation. Here we report that insulin receptor (IR), an integral membrane protein, directly phosphorylates the CNGA1 subunit of CNG channels that in turn affects the function of these channels negatively. The IR phosphorylates Tyr 498 and Tyr 503 residues on CNGA1 that are situated at the membrane-cytoplasmic interface. The IR tyrosine kinase activity is essential for the inhibition of CNG channel. To maintain the channels in an off state, it is necessary not only to have a precise balance of the cGMP levels but also to have a control on the cGMP sensitivity of the CNG channels itself. In this study, we observed that the channel opens at a lower concentration of cGMP in IR Ϫ/Ϫ mice. These studies suggest that IR regulates the modulation of CNG channel activity in vivo.cyclic nucleotide gated channels; insulin receptor; rod outer segments; phosphorylation; guanosine 3=,5=-cyclic monophosphate CYCLIC NUCLEOTIDE GATED (CNG) channels play an important role in visual and olfactory transduction (1,7,15,22). These are crucial for generating the light response in photoreceptors and are directly and cooperatively gated by cGMP. These are critical elements in the maintenance of accurate balance of pace and sensitivity required for phototransduction and play a vital role in photoreceptor homeostasis. CNG channels respond to slight alterations in cytosolic cGMP and have very swift gating kinetics. They transduce a decrease in cGMP into hyperpolarization during the light response and vice versa. These heteromeric, nonselective cation channels in rods are comprised of three ␣ (CNGA1)-and one ␤ (CNGB1)-subunits (39). The expressed homotetramers of ␣-subunits of CNG channels are also equally functional (27). They contain an NH 2 -terminal and a large COOH-terminal nucleotide binding cytoplasmic domain. The critical roles played by CNG channels necessitate comprehensive regulation of its function at several regulatory points. The sensitivity of CNG channel toward cGMP has been extensively studied and is shown to be regulated by several factors other than the cGMP availability like phosphorylation state (18, 26), divalent cations (10, 14), Ca 2ϩ /calmodulin (13, 17), diacylglycerol (9), and phospholipids (41). We have reported previously that Grb14, an insulin receptor (IR)-binding protein, directly binds to the COOHterminal region (CTR) of CNGA1 subunit and inhibits channel activity in a light-dependent manner (11). The interaction is mediated through a Ras-associating domain of Grb14 binding to Ras-like domain in CNGA1 (11,12,36). Our studies also suggest that Grb14 is a competitive inhibitor of cGMP, and thereby it facilitates the closure of the channel to an off state (11). The interaction between Grb14 and CN...

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