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J. Biol. Chem., Vol. 283, Issue 18, 11954-11963, May 2, 2008

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S1P₁ Receptor Localization Confers Selectivity for G_i-mediated cAMP and Contractile Responses^*

Christopher Kable Means, Shigeki Miyamoto, Jerold Chun^¶, and Joan Heller Brown¹

From the Biomedical Sciences Graduate Program and Department of Pharmacology, University of California, San Diego, California 92093-0636 and the ^¶Department of Molecular Biology, The Scripps Research Institute, La Jolla, California 92037

Adult mouse ventricular myocytes express S1P₁, S1P₂, and S1P₃ receptors. S1P activates Akt and ERK in adult mouse ventricular myocytes through a pertussis toxin-sensitive (G_i/o-mediated) pathway. Akt and ERK activation by S1P are reduced 30% in S1P₃ and 60% in S1P₂ receptor knock-out myocytes. With combined S1P_2,3 receptor deletion, activation of Akt is abolished and ERK activation is reduced by nearly 90%. Thus the S1P₁ receptor, while present in S1P_2,3 receptor knock-out myocytes, is unable to mediate Akt or ERK activation. In contrast, S1P induces pertussis toxin-sensitive inhibition of isoproterenol-stimulated cAMP accumulation in both WT and S1P_2,3 receptor knock-out myocytes demonstrating that the S1P₁ receptor can functionally couple to G_i. An S1P₁ receptor selective agonist, SEW2871, also decreased cAMP accumulation but failed to activate ERK or Akt. To determine whether localization of the S1P₁ receptor mediates this signaling specificity, methyl-β-cyclodextrin (MβCD) treatment was used to disrupt caveolae. The S1P₁ receptor was concentrated in caveolar fractions, and associated with caveolin-3 and this localization was disrupted by MβCD. S1P-mediated activation of ERK or Akt was not diminished but inhibition of cAMP accumulation by S1P and SEW2871 was abolished by MβCD treatment. S1P inhibits the positive inotropic response to isoproterenol and this response is also mediated through the S1P₁ receptor and lost following caveolar disruption. Thus localization of S1P₁ receptors to caveolae is required for the ability of this receptor to inhibit adenylyl cyclase and contractility but compromises receptor coupling to Akt and ERK.

Received for publication, September 5, 2007 , and in revised form, February 5, 2008.

Note Added in Proof—A paper that appeared while this manuscript was under review reports experiments using an S1P1 receptor agonist antibody to demonstrate that the S1P1 receptor can activate Akt and thus protect adult mouse myocytes from hypoxia (53).

^* This work was supported by National Institutes of Health Grants HL28143 and HL46345 (to J. H. B.), and NS048478 and DA019674 (to J. C.) and an American Heart Association predoctoral fellowship (to C. K. M.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S2.

¹ To whom correspondence should be addressed: 9500 Gilman Dr., La Jolla, CA 92093-0636. E-mail: jhbrown{at}ucsd.edu.

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