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Long Isoform of Myosin Light Chain Kinase Interacts with Calcium Release‐Activated Calcium Channel Constituents to Induce an Amplified and Protracted Increase in Intracellular Calcium

Stromal interaction molecule 1 (STIM1) induces calcium (Ca2+) entry by activating transient receptor potential canonical (TRPC) channel‐mediated store‐operated calcium (SOC) entry or ORAI1 mediated Ca2+ release‐activated Ca2+(CRAC) entry. However, mechanisms regulating STIM1 interaction with ORAI1/TRPC1 remains unclear. Myosin light chain kinase (MLCK)‐210, a Ca2+‐calmodulin dependent long isoform of MLCK, contains domains at N‐terminus which mediates protein‐protein interaction. We tested the hypothesis that MLCK through its N‐terminus interacts with STIM1, ORAI1 and TRPC1 leading to amplified and protracted increase in Ca2+ entry. We show that thapsigargin, which activates SOC as well as CRAC channels, induce markedly attenuated increase in Ca2+ entry in MLCK‐210−/− endothelial cells (ECs). Restoring N‐terminus but not C‐terminus of MLCK‐210 rescued Ca2+ entry in MLCK‐210−/− ECs. Over expression of N‐MLCK‐210 mutant in wild type ECs rapidly enhanced Ca2+ entry which had a steep slope quite distinct than vector expressing ECs. Interestingly, MLCK‐210 interacted with ORAI1, STIM1 and TRPC1 under basal condition and the interaction further increased following thapsigargin stimulation of ECs. These observations suggest that MLCK‐210 may facilitate STIM1 interaction with ORAI1 and TRPC1 to amplify and protract Ca2+entry in ECs