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J. Biol. Chem. 279 (17): 16903-16906

© 2004 by The American Society for Biochemistry and Molecular Biology, Inc.

ACCELERATED PUBLICATIONS

Guanylyl Cyclase-activating Proteins (GCAPs) Are Ca2+/Mg2+ Sensors

IMPLICATIONS FOR PHOTORECEPTOR GUANYLYL CYCLASE (RetGC) REGULATION IN MAMMALIAN PHOTORECEPTORS*

Igor V. Peshenko, and Alexander M. Dizhoor{ddagger}

Hafter Research Laboratory, Pennsylvania College of Optometry, Elkins Park, Pennsylvania 19027

Abstract: Guanylyl cyclase-activating proteins (GCAP) are EF-hand Ca2+-binding proteins that activate photoreceptor guanylyl cyclase (RetGC) in the absence of Ca2+ and inhibit RetGC in a Ca2+-sensitive manner. The reported data for the RetGC inhibition by Ca2+/GCAPs in vitro are in disagreement with the free Ca2+ levels found in mammalian photoreceptors (Woodruff, M. L., Sampath, A. P., Matthews, H. R., Krasnoperova, N. V., Lem, J., and Fain, G. L. (2002) J. Physiol. (Lond.) 542, 843–854). We have found that binding of Mg2+ dramatically affects both Ca2+-dependent conformational changes in GCAP-1 and Ca2+ sensitivity of RetGC regulation by GCAP-1 and GCAP-2. Lowering free Mg2+ concentrations ([Mg]f) from 5.0 mM to 0.5 mM decreases the free Ca2+ concentration required for half-maximal inhibition of RetGC ([Ca]1/2) by recombinant GCAP-1 and GCAP-2 from 1.3 and 0.2 µM to 0.16 and 0.03 µM, respectively. A similar effect of Mg2+ on Ca2+ sensitivity of RetGC by endogenous GCAPs was observed in mouse retina. Analysis of the [Ca]1/2 changes as a function of [Mg]f in mouse retina shows that the [Ca]1/2 becomes consistent with the range of 23–250 nM free Ca2+ found in mouse photoreceptors only if the [Mg]f in the photoreceptors is near 1 mM. Our data demonstrate that GCAPs are Ca2+/Mg2+ sensor proteins. While Ca2+ binding is essential for cyclase activation and inhibition, Mg2+ binding to GCAPs is critical for setting the actual dynamic range of RetGC regulation by GCAPs at physiological levels of free Ca2+.

Received for publication February 8, 2004.

* This work was supported by National Institutes of Health Grant EY11522 and by the Pennsylvania Lions Sight Conservation and Eye Research Foundation. 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.

{ddagger} A Martin and Florence Hafter Professor of Pharmacology. To whom correspondence should be addressed: Pennsylvania College of Optometry, 8360 Old York Rd., Elkins Park, PA 19027. E-mail: adizhoor{at}pco.edu.

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