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J. Biol. Chem., Vol. 283, Issue 8, 4808-4817, February 22, 2008

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Slo1 Caveolin-binding Motif, a Mechanism of Caveolin-1-Slo1 Interaction Regulating Slo1 Surface Expression^*

Abderrahmane Alioua¹², Rong Lu¹, Yogesh Kumar, Mansoureh Eghbali, Pallob Kundu, Ligia Toro^||3, and Enrico Stefani^¶||3

From the Departments of Anesthesiology, Molecular & Medical Pharmacology, and ^¶Physiology, the ^||Brain Research Institute, and Cardiovascular Research Laboratories, UCLA, Los Angeles, California 90095-1778

The large conductance, voltage- and Ca²⁺-activated potassium (MaxiK, BK) channel and caveolin-1 play important roles in regulating vascular contractility. Here, we hypothesized that the MaxiK -subunit (Slo1) and caveolin-1 may interact with each other. Slo1 and caveolin-1 physiological association in native vascular tissue is strongly supported by (i) detergent-free purification of caveolin-1-rich domains demonstrating a pool of aortic Slo1 co-migrating with caveolin-1 to light density sucrose fractions, (ii) reverse co-immunoprecipitation, and (iii) double immunolabeling of freshly isolated myocytes revealing caveolin-1 and Slo1 proximity at the plasmalemma. In HEK293T cells, Slo1-caveolin-1 association was unaffected by the smooth muscle MaxiK β1-subunit. Sequence analysis revealed two potential caveolin-binding motifs along the Slo1 C terminus, one equivalent, ¹⁰⁰⁷YNMLCFGIY¹⁰¹⁵, and another mirror image, ⁵³⁷YTEYLSSAF⁵⁴⁵, to the consensus sequence, XXXXXX. Deletion of ¹⁰⁰⁷YNMLCFGIY¹⁰¹⁵ caused 80% loss of Slo1-caveolin-1 association while preserving channel normal folding and overall Slo1 and caveolin-1 intracellular distribution patterns. ⁵³⁷YTEYLSSAF⁵⁴⁵ deletion had an insignificant dissociative effect. Interestingly, caveolin-1 coexpression reduced Slo1 surface and functional expression near 70% without affecting channel voltage sensitivity, and deletion of ¹⁰⁰⁷YNMLCFGIY¹⁰¹⁵ motif obliterated channel surface expression. The results suggest ¹⁰⁰⁷YNMLCFGIY¹⁰¹⁵ possible participation in Slo1 plasmalemmal targeting and demonstrate its role as a main mechanism for caveolin-1 association with Slo1 potentially serving a dual role: (i) maintaining channels in intracellular compartments downsizing their surface expression and/or (ii) serving as anchor of plasma membrane resident channels to caveolin-1-rich membranes. Because the caveolin-1 scaffolding domain is juxtamembrane, it is tempting to suggest that Slo1-caveolin-1 interaction facilitates the tethering of the Slo1 C-terminal end to the membrane.

Received for publication, November 30, 2007

^* This work was supported by National Institutes of Health Grants HL54970 and HL77705 (to L. T.), HD046510 (to E. S.), and P01-HL080111 (to E. S. and L. T.) and by American Heart Association National Center Grants 0435084N (to A. A.) and 0435116N (to M. E.). 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 Both authors contributed equally to this work.

³ Co-senior authors.

² To whom correspondence should be addressed: Dept. of Anesthesiology, BH-509A CHS, UCLA, Los Angeles, CA 90095-1778. Tel.: 310-794-7810; Fax: 310-825-5379; E-mail: aalioua{at}ucla.edu.

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