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The neurohypophyseal hormone oxytocin (OT) regulates biologic functions in both peripheral tissues and the central nervous system. In the central nervous system, OT influences social processes, including peer relationships, maternal-infant bonding, and affiliative social relationships. In mammals, the nonapeptide OT structure is highly conserved with leucine in the eighth position (Leu 8 -OT). In marmosets ( Callithrix ), a nonsynonymous nucleotide substitution in the OXT gene codes for proline in the eighth residue position (Pro 8 -OT). OT binds to its cognate G protein-coupled receptor (OTR) and exerts diverse effects, including stimulation (G s ) or inhibition (G i/o ) of adenylyl cyclase, stimulation of potassium channel currents (G i ), and activation of phospholipase C (G q ). Chinese hamster ovary cells expressing marmoset or human oxytocin receptors (mOTRs or hOTRs, respectively) were used to characterize OT signaling. At the mOTR, Pro 8 -OT was more efficacious than Leu 8 -OT in measures of G q activation, with both peptides displaying subnanomolar potencies. At the hOTR, neither the potency nor efficacy of Pro 8 -OT and Leu 8 -OT differed with respect to G q signaling. In both mOTR- and hOTR-expressing cells, Leu 8 -OT was more potent and modestly more efficacious than Pro 8 -OT in inducing hyperpolarization. In mOTR cells, Leu 8 -OT-induced hyperpolarization was modestly inhibited by pretreatment with pertussis toxin (PTX), consistent with a minor role for G i/o activation; however, the Pro 8 -OT response in mOTR and hOTR cells was PTX insensitive. These findings are consistent with membrane hyperpolarization being largely mediated by a G q signaling mechanism leading to Ca 2+ -dependent activation of K + channels. Evaluation of the influence of apamin, charybdotoxin, paxilline, and TRAM-34 demonstrated involvement of both intermediate and large conductance Ca 2+ -activated K + channels.

molecular pharmacology

A Comparison of the Ability of Leu8- and Pro8-Oxytocin to Regulate Intracellular Ca2+ and Ca2+-Activated K+ Channels at Human and Marmoset Oxytocin Receptors