Differential contribution of ORAI and TRPC channels to parity-dependent uterine oxytocin response

Introduction: Pregnancy induces persistent changes in uterine Ca 2+ handling, resulting in a differential contractile response to oxytocin (OT) between virgin (V) and proven breeder (PB) rats. Specifically, in the absence of blockers, AUC and frequency are higher in PB strips, while amplitudes are higher in V strips. Store-operated Ca 2+ entry (SOCE) channels, including ORAI and the TRPC family, are major mediators of myometrial excitability. Previous work established that the ORAI component of SOCE is an important determinant of this parity-dependent difference, while TRPC3 plays a lesser role. Hypothesis: Here, we extend this study to investigate the hypothesis that other TRPC subtypes expressed in the uterus (TRPC1, 4, 5, and 6) might be more significantly involved. Methods: Motility experiments were conducted on uterine strips from non-pregnant V and PB female rats at proestrus. OT dose-response curves (1E-10 to 1E-5 M) were recorded following preconditioning with Pico145 (5 nM, TRPC1, 4, and 5 blocker) and BI749327 (200 nM, TRPC6 blocker). Results: AUC, frequency, and amplitude were measured. With Pico145, the AUC difference was attenuated, though maximal amplitude remained significantly higher in V than in PB (P=0.003), and frequency curves retained the PB dominance (P< 0.01). With BI749327, the AUC and frequency parameters became statistically similar, but amplitude remained higher in V (P=0.001). Compared to the comprehensive attenuation observed with the ORAI blocker (Synta66, 1 µM), the TRPC blockers only partially rescued the parity-dependent differences. We conclude that within the SOCE pathway, the ORAI channel component is the most significant molecular determinant of the differential contractile response to OT between V and PB rat uteri. This study was supported by a Kenneth Suarez Fellowship to DB and an MWU intramural fund to MP. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.