4.5 Article

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

Journal

MOLECULAR PHARMACOLOGY
Volume 95, Issue 4, Pages 376-385

Publisher

AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
DOI: 10.1124/mol.118.114744

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Funding

  1. National Institutes of Health Eunice Kennedy Shriver National Institute of Child Health and Human Development [R01-HD089147]

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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 non-apeptide 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) 10 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 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 channels.

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