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The Journal of Neuroscience, April 26, 2006, 26(17):4472-4480; doi:10.1523/JNEUROSCI.4775-05.2006

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Cellular/Molecular
GAP-Independent Termination of Photoreceptor Light Response by Excess Subunit of the cGMP-Phosphodiesterase

Steven H. Tsang,¹ Michael L. Woodruff,² Ching-Kang Chen,³ Clyde Y. Yamashita,⁴ Marianne C. Cilluffo,² Anjali L. Rao,³ Debora B. Farber,⁴ and Gordon L. Fain^2,4

¹Brown Glaucoma Laboratory, Department of Pathology, Center for Neurobiology and Behavior, College of Physicians and Surgeons, Columbia University, New York, New York 10032, ²Department of Physiological Science, University of California Los Angeles (UCLA), Los Angeles, California 90095-1606, ³Department of Biochemistry, Virginia Commonwealth University, Richmond, Virginia 23298-0614, and ⁴Jules Stein Eye Institute, UCLA School of Medicine, Los Angeles, California 90095-7000

Correspondence should be addressed to Prof. Gordon L. Fain, Department of Physiological Science, University of California Los Angeles, 3836 Life Sciences, Los Angeles, CA 90095-1606. Email: gfain{at}ucla.edu

We have generated a mouse with rod photoreceptors overexpressing the inhibitory subunit (PDE6) of the photoreceptor G-protein effector cGMP phosphodiesterase (PDE6). PDE6 overexpression decreases the rate of rise of the rod response at dim intensities, indicating a reduction in the gain of transduction that may be the result of cytoplasmic PDE6 binding to activated transducin GTP (T-GTP) before the T-GTP binds to endogenous PDE6. Excess PDE6 also produces a marked acceleration in the falling phase of the light response and more rapid recovery of sensitivity and circulating current after prolonged light exposure. These effects are not mediated by accelerating GTP hydrolysis through the GAP (GTPase activating protein) complex, because the decay of the light response is also accelerated in rods that overexpress PDE6 but lack RGS9. Our results show that the PDE6 binding sites of PDE6 and are accessible to excess (presumably cytoplasmic) PDE6 in the light, once endogenous PDE6 has been displaced from its binding site by T-GTP. They also suggest that in the presence of T-GTP, the PDE6 remains attached to the rest of the PDE6 molecule, but after conversion of T-GTP to T-GDP, the PDE6 may dissociate from the PDE6 and exchange with a cytoplasmic pool. This pool may exist even in wild-type rods and may explain the decay of rod photoresponses in the presence of nonhydrolyzable analogs of GTP.

Key words: rod; phototransduction; retina; phosphodiesterase; G-protein; RGS protein

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Received Nov. 7, 2005; revised March 13, 2006; accepted March 16, 2006.

Correspondence should be addressed to Prof. Gordon L. Fain, Department of Physiological Science, University of California Los Angeles, 3836 Life Sciences, Los Angeles, CA 90095-1606. Email: gfain{at}ucla.edu

This article has been cited by other articles:

				R. J. Davis, J. Tosi, K. M. Janisch, J. M. Kasanuki, N.-K. Wang, J. Kong, I. Tsui, M. Cilluffo, M. L. Woodruff, G. L. Fain, et al. Functional Rescue of Degenerating Photoreceptors in Mice Homozygous for a Hypomorphic cGMP Phosphodiesterase 6 b Allele (Pde6bH620Q) Invest. Ophthalmol. Vis. Sci., November 1, 2008; 49(11): 5067 - 5076. [Abstract] [Full Text] [PDF]

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