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J. Biol. Chem., Vol. 282, Issue 13, 9865-9873, March 30, 2007

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G-protein-coupled Receptor Rhodopsin Regulates the Phosphorylation of Retinal Insulin Receptor^*

Ammaji Rajala, Robert E. Anderson^¶, Jian-Xing Ma^¶||, Janis Lem^**, Muayyad R. Al-Ubaidi^¶, and Raju V. S. Rajala, Recipient of a Career Development Award from Research to Prevent Blindness, Inc^¶1

From the Departments of Ophthalmology, ^¶Cell Biology, and ^||Medicine and the Dean A. McGee Eye Institute, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104 and the ^**Department of Ophthalmology, New England Medical Center and Tufts University School of Medicine, Boston, Massachusetts 02111

We have shown previously that phosphoinositide 3-kinase in the retina is activated in vivo through light-induced tyrosine phosphorylation of the insulin receptor (IR). The light effect is localized to photoreceptor neurons and is independent of insulin secretion (Rajala, R. V., McClellan, M. E., Ash, J. D., and Anderson, R. E. (2002) J. Biol. Chem. 277, 43319–43326). These results suggest that there exists a cross-talk between phototransduction and other signal transduction pathways. In this study, we examined the stage of phototransduction that is coupled to the activation of the IR. We studied IR phosphorylation in mice lacking the rod-specific -subunit of transducin to determine if phototransduction events are required for IR activation. To confirm that light-induced tyrosine phosphorylation of the IR is signaled through bleachable rhodopsin, we examined IR activation in retinas from RPE65^-/- mice that are deficient in opsin chromophore. We observed that IR phosphorylation requires the photobleaching of rhodopsin but not transducin signaling. To determine whether the light-dependent activation of IR is mediated through the rod or cone transduction pathway, we studied the IR activation in mice lacking opsin, a mouse model of pure cone function. No light-dependent activation of the IR was found in the retinas of these mice. We provide evidence for the existence of a light-mediated IR pathway in the retina that is different from the known insulin-mediated pathway in nonneuronal tissues. These results suggest that IR phosphorylation in rod photoreceptors is signaled through the G-protein-coupled receptor rhodopsin. This is the first study demonstrating that rhodopsin can initiate signaling pathway(s) in addition to its classical phototransduction.

Received for publication, September 13, 2006 , and in revised form, January 9, 2007.

^* This work was supported by National Institutes of Health Grants EY016507, EY00871, EY04149, EY12190, and RR17703 and grants from Research to Prevent Blindness Inc. and the Foundation Fighting Blindness, Inc. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: University of Oklahoma Health Sciences Center, 608 Stanton L. Young Blvd., Oklahoma City, OK 73104. Tel.: 405-271-8255; Fax: 405-271-8128; E-mail: raju-rajala{at}ouhsc.edu.

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