Parity Dependent Differential Uterine Oxytocin Response: A Prominent Role for ORAI Channels

Introduction: Pregnancy permanently affects the health and function of the uterus, specifically the intracellular Ca 2+ management, as proven by the differential response to oxytocin in virgin and proven breeder rats we have previously described. Hypothesis: Here, we propose that store operated Ca 2+ entry (SOCE) channels, ORAI and TRPC channels, contribute to the parity-dependent modulation of the uterine contractile responses to oxytocin. Methods: Motility experiments were conducted on uterine strips from virgin (V) and proven breeder (PB) non pregnant female 18-week-old rats euthanized at proestrus. Dose response curves to oxytocin (10E-10 to 10E-5 M) in the presence of the highly specific ORAI blocker synta66 (1 µM) and TRPC3 blocker Pyr3 (1 µM) were recorded. Area under the curve (AUC), frequency, and amplitude of contractions were measured. T-tests and ANOVA two ways were used for statistical analysis. Results: With syntax 66, previously observed differential response to oxytocin was greatly attenuated. The, the curve parameters (minimum, maximum, range of increase, and EC50) measured for AUC and frequency were similar (P>0.05). The EC50 of the amplitude curve was smaller for PB, while both minimum and maximum of the curve were greater than in V samples. In all our earlier experiments the amplitude response was stronger in V strips. Conversely, preconditioning with Pyr3 had a much smaller effect. The maximal AUC response to oxytocin was indeed similar in V and PB, however the minimum and range recorded resembled those observed in the absence of inhibitors. The amplitude and frequency curves followed the trends observed in the absence of inhibitors. Conclusions: ORAI channels, not TRPC3, appear to significantly contribute to the differential response of virgin and proven breeder rats to oxytocin. Further investigation of other TRPC channels will clarify the overall role of SOCE in this phenomenon. This study was supported by a Kenneth Suarez Fellowship to VG and an MWU intramural fund to MP. This abstract was presented at the American Physiology Summit 2025 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.