A comparison of the ability of Leu 8 - And pro 8 -oxytocin to regulate intracellular Ca 21 and Ca 21 -activated K 1 channels at human and marmoset oxytocin receptors S

Marsha L. Pierce, Suneet Mehrotra, Aaryn C. Mustoe, Jeffrey A. French, Thomas F. Murray

Research output: Contribution to journalArticle

Abstract

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 nonsynon-ymous 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 21 -dependent activation of K 1 channels. Evaluation of the influence of apamin, charybdotoxin, paxilline, and TRAM-34 demonstrated involvement of both intermediate and large conductance Ca 21 -activated K 1 channels.

Original languageEnglish (US)
Pages (from-to)376-385
Number of pages10
JournalMolecular Pharmacology
DOIs
StatePublished - Apr 1 2019

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Callithrix
Oxytocin
Pertussis Toxin
Central Nervous System
Posterior Pituitary Hormones
Charybdotoxin
Apamin
human OXTR protein
Gly-Lys-Arg-oxytocin
Potassium Channels
Type C Phospholipases
Cricetulus
Adenylyl Cyclases
Proline
Leucine
Mammals
Ovary
Nucleotides
Mothers
Peptides

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology

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A comparison of the ability of Leu 8 - And pro 8 -oxytocin to regulate intracellular Ca 21 and Ca 21 -activated K 1 channels at human and marmoset oxytocin receptors S . / Pierce, Marsha L.; Mehrotra, Suneet; Mustoe, Aaryn C.; French, Jeffrey A.; Murray, Thomas F.

In: Molecular Pharmacology, 01.04.2019, p. 376-385.

Research output: Contribution to journalArticle

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abstract = "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 nonsynon-ymous 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 21 -dependent activation of K 1 channels. Evaluation of the influence of apamin, charybdotoxin, paxilline, and TRAM-34 demonstrated involvement of both intermediate and large conductance Ca 21 -activated K 1 channels.",
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