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TRPC6 knock‐down specifically attenuates diacylglycerol‐mediated elevation of intracellular calcium in human myometrial cells

Human myometrium exhibits receptor‐, store‐ and diacylglycerol (OAG)‐mediated extracellular Ca2+‐dependent increases in intracellular Ca2+ ([Ca2+]i)(SRCE) and expresses TRPC mRNAs, predominantly TRPC1, 4, and 6, that have been implicated in SRCE. To determine the role of TRPC6 in myometrial SRCE, short hairpin RNA constructs that effectively targeted a TRPC6 mRNA reporter for degradation were designed and one sequence was used to produce an adenovirus construct (TC6sh1). TC6sh1 reduced TRPC6 mRNA but not TRPC1, 3, 4, 5 or 7 mRNAs in PHM1‐41 myometrial cells. Compared to uninfected cells or cells infected with empty vector, the increase in [Ca2+]i in response to OAG was specifically inhibited by TC6sh1; SRCE responses elicited by either oxytocin or thapsigargin were not changed. Similar findings were observed in primary pregnant human myometrial cells. When PHM1‐41 cells were activated by OAG in the absence of extracellular Na+, the increase in [Ca2+]i was partially reduced. Furthermore, pretreatment with nifedipine, an L‐type calcium channel blocker, also reduced the OAG‐induced [Ca2+]i increase. These findings suggest that OAG targets channels containing TRPC6 in myometrial cells and that these channels act, in part, in an indirect manner via enhanced Na+ entry and activation of voltage‐dependent Ca2+ entry to promote elevation of intracellular Ca2+. Supported by March of Dimes #6‐FY05‐77 and HD38970.