Abstract
The neurohypophyseal hormone oxytocin (OT) regulates biological functions in both peripheral tissues and the central nervous system (CNS). In the CNS, 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 8th position (Leu8-OT). In marmosets (Callithrix) a nonsynonymous nucleotide substitution in the OXT gene codes for proline in the 8th residue position (Pro8-OT). OT binds to its cognate G protein-coupled receptor (OTR) and exerts diverse effects, including stimulation (Gs) or inhibition (Gi/o) of adenylyl cyclase, stimulation of potassium channel currents (Gi) and activation of phospholipase C (Gq). CHO cells expressing marmoset (mOTR) or human (hOTR) oxytocin receptors were used to characterize OT signaling. At mOTR, Pro8-OT was more efficacious than Leu8-OT in measures of Gq activation with both peptides displaying subnanomolar potencies. At hOTR, neither potency nor efficacy of Pro8-OT and Leu8-OT differed with respect to Gq signaling. In both mOTR- and hOTR-expressing cells Leu8-OT was more potent and modestly more efficacious than Pro8-OT in inducing hyperpolarization. In mOTR cells, Leu8-OT-induced hyperpolarization was modestly inhibited by pretreatment with pertussis toxin (PTX) consistent with a minor role for Gi/o-activation; however, the Pro8-OT response in mOTR and hOTR cells was PTX-insensitive. These findings are consistent with membrane hyperpolarization being largely mediated by a Gq signaling mechanism leading to Ca2+-dependent activation of K+ channels. Evaluation of the influence of apamin, charybdotoxin, paxilline and TRAM-34 demonstrated involvement of both intermediate and large conductance Ca2+-activated K+ channels.
- Calcium-activated potassium channels
- G protein-coupled receptors (GPCRs)
- G proteins (GTP-binding proteins)
- Oxytocin
- The American Society for Pharmacology and Experimental Therapeutics