Background: Some inherited defects in NHERF1 are associated with high phosphate (P i ) excretion and skeletal abnormalities. Results: NHERF1 forms a multiprotein complex with Npt2a and ezrin. Mutants fail to assemble this ternary complex.
Conclusion:The NHERF1 ternary complex is required for PTH-sensitive P i transport. Significance: NHERF1 mutations may cause disease processes through structural changes that prevent assembly of multiprotein complexes.
Adult mouse ventricular myocytes (AMVMs) express S1P1, S1P2, and S1P3 receptors. S1P activates Akt and ERK in AMVMs through a pertussis toxin (PTX)‐sensitive (Gi‐mediated) pathway. S1P‐mediated activation of ERK and Akt is partially reduced in both S1P2 and S1P3 receptor null AMVMs and abolished in S1P2,3 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 S1P2,3 null myocytes, demonstrating that the S1P1 receptor also couples to Gi. Similarly an S1P1 receptor selective agonist, SEW2871, also decreased iso‐stimulated cAMP accumulation but failed to activate either ERK or Akt. To determine whether localization of the S1P1 receptor and its effectors is important in mediating this signaling specificity, the caveolae disrupting agent methyl‐β‐cyclodextrin (MβCD) was used. The S1P1 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 S1P1 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)
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