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 (Gi/o-mediated) pathway. Akt and ERK activation by S1P are reduced ∼30% in S1P3 and 60% in S1P2 receptor knock-out myocytes. With combined S1P2,3 receptor deletion, activation of Akt is abolished and ERK activation is reduced by nearly 90%. Thus the S1P1 receptor, while present in S1P2,3 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 S1P2,3 receptor knock-out myocytes demonstrating that the S1P1 receptor can functionally couple to Gi. 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
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