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Lipid oxidation products, including lysophosphatidylcholine (lysoPC), activate canonical transient receptor potential 6 (TRPC6) channels leading to inhibition of endothelial cell (EC) migration in vitro and delayed EC healing of arterial injuries in vivo. The precise mechanism through which lysoPC activates TRPC6 channels is not known, but calmodulin (CaM) contributes to the regulation of TRPC channels. Using site-directed mutagenesis, cDNAs were generated in which Tyr⁹⁹ or Tyr¹³⁸ of CaM was replaced with Phe, generating mutant CaM, Phe⁹⁹-CaM, or Phe¹³⁸-CaM, respectively. In ECs transiently transfected with pcDNA3.1-myc-His-Phe⁹⁹-CaM, but not in ECs transfected with pcDNA3.1-myc-His-Phe¹³⁸-CaM, the lysoPC-induced TRPC6-CaM dissociation and TRPC6 externalization was disrupted. Also, the lysoPC-induced increase in intracellular calcium concentration was inhibited in ECs transiently …