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S1P receptor localization confers selectivity for G i mediated signaling pathways
Author(s) -
Means Chris,
Miyamoto Shigeki,
Chun Jerold,
Brown Joan Heller
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.727.6
Subject(s) - mapk/erk pathway , microbiology and biotechnology , receptor , protein kinase b , adenylyl cyclase , signal transduction , chemistry , g protein coupled receptor , pi3k/akt/mtor pathway , pertussis toxin , agonist , biology , endocrinology , medicine , g protein , biochemistry
Adult mouse ventricular myocytes (AMVMs) express S1P 1 , S1P 2 , and S1P 3 receptors. S1P activates Akt and ERK in AMVMs through a pertussis toxin (PTX)‐sensitive (G i ‐mediated) pathway. S1P‐mediated activation of ERK and Akt is partially reduced in both S1P 2 and S1P 3 receptor null AMVMs and abolished in S1P 2,3 receptor null AMVMs. In addition S1P treatment leads to PTX‐sensitive inhibition of isoproterenol (iso)‐stimulated cAMP accumulation in WT myocytes, and this response in unchanged in S1P 2,3 null myocytes, demonstrating that the S1P 1 receptor also couples to G i . Similarly an S1P 1 receptor selective agonist, SEW2871, also decreased iso‐stimulated cAMP accumulation but failed to activate either ERK or Akt. To determine whether localization of the S1P 1 receptor and its effectors is important in mediating this signaling specificity, the caveolae disrupting agent methyl‐β‐cyclodextrin (MβCD) was used. The S1P 1 receptor was concentrated in caveolar fractions and this localization was disrupted by MβCD treatment. MβCD did not prevent S1P‐mediated activation of ERK or Akt, but fully abolished the inhibition of cAMP accumulation and negative inotropic effects of both S1P and SEW2871. Together, the data indicate that localization of S1P 1 receptors to caveolae is required for this receptor to inhibit adenylyl cyclase and decrease contractility, yet compromises the coupling of this receptor to Akt and ERK pathways. This work was supported by National Institutes of Health Grants HL28143 and HL46345 (to J.H. Brown), NS048478 and DA019674 (to J. Chun), and by an American Heart Association predoctoral fellowship (to C.K. Means)