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Caveolin-1 Regulates Store-Operated Ca²⁺ Influx by Binding of Its Scaffolding Domain to Transient Receptor Potential Channel-1 in Endothelial Cells

Department of Pharmacology and Center for Lung and Vascular Biology, College of Medicine, University of Illinois at Chicago, Chicago, Illinois (A.M.K., R.D.M., R.A.S., A.B.M., C.T.); and Department of Pharmacology/Toxicology, Boonshoft School of Medicine, Wright State, University, Dayton, Ohio (D.R.C.)

Caveolin-1 associates with store-operated cation channels (SOC) in endothelial cells. We examined the role of the caveolin-1 scaffolding domain (CSD) in regulating the SOC [i.e., transient receptor potential channel-1 (TRPC1)] in human pulmonary artery endothelial cells (HPAECs). We used the cellpermeant antennapedia (AP)-conjugated CSD peptide, which competes for protein binding partners with caveolin-1, to assess the interactions of caveolin-1 with TRPC1 and its consequences on thrombin-induced Ca²⁺ influx. We observed that AP-CSD peptide markedly reduced thrombin-induced Ca²⁺ influx via SOC in HPAECs in contrast to control peptide. AP-CSD also suppressed thapsigargin-induced Ca²⁺ influx. Streptavidin-bead pull-down assay indicated strong binding of biotin-labeled AP-CSD peptide to TRPC1. Immunoprecipitation studies demonstrated an interaction between endogenous TRPC1 and ectopically expressed hemagglutinin-tagged CSD. Analysis of the deduced TRPC1 amino acid sequence revealed the presence of CSD binding consensus sequence in the TRPC1 C terminus. We also observed that an AP-TRPC1 peptide containing the CSD binding sequence markedly reduced the thrombin-induced Ca²⁺ influx. We identified the interaction between biotin-labeled AP-TRPC1 C terminus peptide and caveolin-1. Thus, these results demonstrate a crucial role of caveolin-1 scaffolding domain interaction with TRPC1 in regulating Ca²⁺ influx via SOC.

Address correspondence to: Dr. Chinnaswamy Tiruppathi, Department of Pharmacology (M/C868), College of Medicine, University of Illinois at Chicago, 835 S. Wolcott Avenue, Chicago, IL 60612. E-mail: tiruc{at}uic.edu

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