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The Journal of Neuroscience, April 15, 2000, 20(8):2792-2799

Do Phosphatidylinositides Modulate Vertebrate Phototransduction?

Kyle B. Womack¹, Sharona E. Gordon², Feng He³, Theodore G. Wensel³, Chin-Chi Lu¹, and Donald W. Hilgemann¹

¹ Department of Physiology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75235-9040, ² Department of Ophthalmology, University of Washington School of Medicine, Seattle, Washington 98195-6485, and ³ Department of Biochemistry, Baylor College of Medicine, Houston, Texas 77030

Mammalian rod cyclic nucleotide gated (CNG) channels (i.e.,  plus  subunits) are strongly inhibited by phosphatidylinositol 4,5-bisphosphate (PIP₂) when they are expressed in Xenopus oocytes and studied in giant membrane patches. Cytoplasmic Mg-ATP inhibits CNG currents similarly, and monoclonal antibodies to PIP₂ reverse the effect and hyperactivate currents. When  subunits are expressed alone, PIP₂ inhibition is less strong; olfactory CNG channels are not inhibited. In giant patches from rod outer segments, inhibition by PIP₂ is intermediate. Other anionic lipids (e.g., phosphatidyl serine and phosphatidic acid), a phosphatidylinositol-specific phospholipase C, and full-length diacylglycerol have stimulatory effects. Although ATP also potently inhibits cGMP-activated currents in rod patches, the following findings indicate that ATP is used to transphosphorylate GMP, generated from cGMP, to GTP. First, a phosphodiesterase (PDE) inhibitor, Zaprinast, blocks inhibition by ATP. Second, inhibition can be rapidly reversed by exogenous regulator of G-protein signaling 9, suggesting G-protein activation by ATP. Third, the reversal of ATP effects is greatly slowed when cyclic inosine 5'-monophosphate is used to activate currents, as expected for slow inosine 5' triphosphate hydrolysis by G-proteins. Still, other results remain suggestive of regulatory roles for PIP₂. First, the cGMP concentration producing half-maximal CNG channel activity (K_1/2) is decreased by PIP₂ antibody in the presence of PDE inhibitors. Second, the activation of PDE activity by several nucleotides, monitored electrophysiologically and biochemically, is reversed by PIP₂ antibody. Third, exogenous PIP₂ can enhance PDE activation by nucleotides.

Key words: cIMP; cyclic nucleotide gated channels; DAG; giant patch; ITP; photoreceptors; phosphatydilinositides; phototransduction; PLC; PIP₂; RGS proteins; rod cells; transphosphorylation

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Copyright © 2000 Society for Neuroscience  0270-6474/00/2082792-08$05.00/0

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