Serotonin Receptors Increase during Pregnancy and Activate Human Myometrial Smooth Muscle in a Src Independent Manner
Abstract Number: BP-1
Abstract Type: Original Research
Introduction: Serotonin (5-hydroxytryptamine, 5-HT) is a neurotransmitter, neuromodulator, and neurohormone. It modulates many behavioral processes through the at least 14 subclasses of the 5-HT receptors. Serotonin receptor-2a (SR-2a) is the only receptor among these receptor subclasses with an effect on contractility. Serotonin is also known to modulate contractions of the uterus; however, the involved signaling pathways have not been studied in detail. Src kinase is a major regulator of focal adhesion turnover and contractility in myometrial muscle (Li et al). The hypothesis of the current study is to determine if Src mediates serotonin-induced contractions and whether serotonin activates the focal adhesion signaling pathway.
Methods: After informed written consent, human uterine samples were collected from patients undergoing cesarean sections. Rat myometrium samples were also collected for comparison. Isometric tension measurements were used to determine the effect of serotonin and the effect of a Src inhibitor on strips of human myometrium.
Results: By using Western immunoblotting, here we demonstrate that the protein levels of the serotonin receptor 2a increase significantly during pregnancy, both in rat and human uterine smooth muscle. We studied ex vivo the contractile effect of serotonin in isometrically contracting human term uterine smooth muscle in a myobath. 10-6M serotonin markedly augments spontaneous contraction and significantly increases the contractility (area under curve AUC of 5 minutes) (baseline 232±66 vs. 1202±324, p=0.02). Stretch of smooth muscle to 1.5x of resting length can also induce contraction to a similar extent as serotonin (AUC 5’ 1801±477). Interestingly, PP2, a Src inhibitor, differentially inhibits stretch induced contraction (AUC 5’ 451±89 vs.1801±477, p=0.03), but not serotonin-induced contraction (AUC 5’ 812±369 vs. 1202±324, p=0.22), indicating that serotonin activates uterine smooth muscle dominantly via Src independent pathways.
Conclusion: In the present study, we used a selective Src inhibitor to determine that the effect of serotonin on isolated strips of myometrium is Src independent. Serotonin is a potent uterotonic agent that may play a key role in the prevention of uterine atony and consequent postpartum hemorrhage.
Li Y, Reznichenko M, Tribe RM, Hess PE, Taggart M, Kim HR, DeGnore JP, Gangopadhyay S and Morgan KG. Stretch Activates Human Myometrium via ERK, Caldesmon and Focal Adhesion Signaling. PLoS ONE 2009; 4(10): e7489.