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J. Biol. Chem., Vol. 281, Issue 36, 26391-26399, September 8, 2006

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Microtubules and Actin Microfilaments Regulate Lipid Raft/Caveolae Localization of Adenylyl Cyclase Signaling Components^*

Brian P. Head, Hemal H. Patel, David M. Roth^¶, Fiona Murray, James S. Swaney, Ingrid R. Niesman^||, Marilyn G. Farquhar^||, and Paul A. Insel^**1

From the Departments of Pharmacology, Anesthesiology, ^||Cellular and Molecular Medicine, and ^**Medicine, University of California, San Diego, La Jolla, California 92093 and ^¶Veterans Affairs San Diego Healthcare System, San Diego, California 92161

Microtubules and actin filaments regulate plasma membrane topography, but their role in compartmentation of caveolae-resident signaling components, in particular G protein-coupled receptors (GPCR) and their stimulation of cAMP production, has not been defined. We hypothesized that the microtubular and actin cytoskeletons influence the expression and function of lipid rafts/caveolae, thereby regulating the distribution of GPCR signaling components that promote cAMP formation. Depolymerization of microtubules with colchicine (Colch) or actin microfilaments with cytochalasin D (CD) dramatically reduced the amount of caveolin-3 in buoyant (sucrose density) fractions of adult rat cardiac myocytes. Colch or CD treatment led to the exclusion of caveolin-1, caveolin-2, ₁-adrenergic receptors (₁-AR), ₂-AR, G_s, and adenylyl cyclase (AC)_5/6 from buoyant fractions, decreasing AC_5/6 and tyrosine-phosphorylated caveolin-1 in caveolin-1 immunoprecipitates but in parallel increased isoproterenol (-AR agonist)-stimulated cAMP production. Incubation with Colch decreased co-localization (by immunofluorescence microscopy) of caveolin-3 and -tubulin; both Colch and CD decreased co-localization of caveolin-3 and filamin (an F-actin cross-linking protein), decreased phosphorylation of caveolin-1, Src, and p38 MAPK, and reduced the number of caveolae/µm of sarcolemma (determined by electron microscopy). Treatment of S49 T-lymphoma cells (which possess lipid rafts but lack caveolae) with CD or Colch redistributed a lipid raft marker (linker for activation of T cells (LAT)) and G_s from lipid raft domains. We conclude that microtubules and actin filaments restrict cAMP formation by regulating the localization and interaction of GPCR-G_s-AC in lipid rafts/caveolae.

Received for publication, March 20, 2006 , and in revised form, June 16, 2006.

^* This work was supported by National Institutes of Health Grants GM66232 and HL66941. 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 To whom correspondence should be addressed: University of California, San Diego, Dept. of Pharmacology, 9500 Gilman Dr., BSB 3076 La Jolla, CA 92093-0636. Tel.: 858-534-2295; Fax: 858-822-1007; E-mail: pinsel{at}ucsd.edu.

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