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J. Biol. Chem., Vol. 279, Issue 21, 22643-22653, May 21, 2004

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Cellular Processing of Cone Photoreceptor Cyclic GMP-gated Ion Channels

A ROLE FOR THE S4 STRUCTURAL MOTIF^*

Maria Paula Faillace, Ramon O. Bernabeu, and Juan I. Korenbrot

From the Department of Physiology, School of Medicine, University of California, San Francisco, California 94143

We examined cellular protein processing and functional expression of photoreceptor cyclic nucleotidegated (CNG) ion channels. In a mammalian cell line, wild type bovine cone photoreceptor channel subunits (bCNGA3) convert from an unglycosylated state, at 90 kDa, to two glycosylated states at 93 and 102 kDa as they transit within the cell to their final location at the plasma membrane. Glycosylation per se is not required to yield functional channels, yet it is a milestone that distinguishes sequential steps in channel protein maturation. CNG ion channels are not gated by membrane voltage although their structure includes the transmembrane S4 motif known to function as the membrane voltage sensor in all voltage-gated ion channels. S4 must be functionally important because its natural mutation in cone photoreceptor CNG channels is associated with achromatopsia, a human autosomal inherited loss of cone function. Point mutation of specific, not all, charged and neutral residues within S4 cause failure of functional channel expression. Cellular channel protein processing fails in every one of the non-functional S4 mutations we studied. Mutant proteins do not reach the 102-kDa glycosylated state and do not arrive at the plasma membrane. They remain trapped within the endoplasmic reticulum and fail to transit out to the Golgi apparatus. Coexpression of cone CNG subunit (CNGB3) does not rescue the consequence of S4 mutations in CNGA3. It is likely that an intact S4 is required for proper protein folding and/or assembly in the endoplasmic reticulum membrane.

Received for publication, January 5, 2004 , and in revised form, March 8, 2004.

^* 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.

To whom correspondence should be addressed: Box 0444, University of California, San Francisco, CA 94143. Tel.: 415-476-1652; Fax: 415-476-4929; E-mail: juan{at}itsa.ucsf.edu.

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