TY - JOUR
T1 - Comparison of the pharmacologic profiles of arginine vasopressin and oxytocin analogs at marmoset, titi monkey, macaque, and human oxytocin receptors
AU - Pierce, Marsha L.
AU - French, Jeffrey A.
AU - Murray, Thomas F.
N1 - Funding Information:
This work was supported by the National Institutes of Health Eunice Kennedy Shriver National Institute of Child Health and Human Development [Grant R01HD089147 ]. We thank Dr. Myron Toews, Nancy Schulte and Dr. Jack Taylor for providing the stably transfected qOTR and tOTR cell lines. We thank Dr. Jeffrey French and Dr. Aaryn Mustoe for providing the AVP, Leu 8 -OT and Pro 8 -OT peptides. We thank Dr. Aaryn Mustoe for helping with some of the experiments. We thank Dr. Suneet Mehrotra for his thoughtful discussions and Ms. Bridget Sefranek for her careful reading of the manuscript.
Funding Information:
This work was supported by the National Institutes of Health Eunice Kennedy Shriver National Institute of Child Health and Human Development [Grant R01HD089147]. We thank Dr. Myron Toews, Nancy Schulte and Dr. Jack Taylor for providing the stably transfected qOTR and tOTR cell lines. We thank Dr. Jeffrey French and Dr. Aaryn Mustoe for providing the AVP, Leu8-OT and Pro8-OT peptides. We thank Dr. Aaryn Mustoe for helping with some of the experiments. We thank Dr. Suneet Mehrotra for his thoughtful discussions and Ms. Bridget Sefranek for her careful reading of the manuscript.
PY - 2020/5
Y1 - 2020/5
N2 - The oxytocin-arginine vasopressin (OT-AVP) ligand-receptor family influences a variety of physiological, behavioral, and social behavioral processes in the brain and periphery. The OT-AVP family is highly conserved in mammals, but recent discoveries have revealed remarkable diversity in OT ligands and receptors in New World Monkeys (NWMs) providing a unique opportunity to assess the effects of genetic variation on pharmacological signatures of peptide ligands. The consensus mammalian OT sequence has leucine in the 8th position (Leu8-OT), whereas a number of NWMs, including the marmoset, have proline in the 8th position (Pro8-OT) resulting in a more rigid tail structure. OT and AVP bind to OT's cognate G-protein coupled receptor (OTR), which couples to various G-proteins (Gi/o, Gq, Gs) to stimulate diverse signaling pathways. CHO cells expressing marmoset (mOTR), titi monkey (tOTR), macaque (qOTR), or human (hOTR) OT receptors were used to compare AVP and OT analog-induced signaling. Assessment of Gq-mediated increase in intracellular calcium (Ca2+) demonstrated that AVP was less potent than OT analogs at OTRs from species whose endogenous ligand is Leu8-OT (tOTR, qOTR, hOTR), relative to Pro8-OT. Likewise, AVP-induced membrane hyperpolarization was less potent at these same OTRs. Evaluation of (Ca2+)-activated potassium (K+) channels using the inhibitors apamin, paxilline, and TRAM-34 demonstrated that both intermediate and large conductance Ca2+-activated K+ channels contributed to membrane hyperpolarization, with different pharmacological profiles identified for distinct ligand-receptor combinations. Understanding more fully the contributions of structure activity relationships for these peptide ligands at vasopressin and OT receptors will help guide the development of OT-mediated therapeutics.
AB - The oxytocin-arginine vasopressin (OT-AVP) ligand-receptor family influences a variety of physiological, behavioral, and social behavioral processes in the brain and periphery. The OT-AVP family is highly conserved in mammals, but recent discoveries have revealed remarkable diversity in OT ligands and receptors in New World Monkeys (NWMs) providing a unique opportunity to assess the effects of genetic variation on pharmacological signatures of peptide ligands. The consensus mammalian OT sequence has leucine in the 8th position (Leu8-OT), whereas a number of NWMs, including the marmoset, have proline in the 8th position (Pro8-OT) resulting in a more rigid tail structure. OT and AVP bind to OT's cognate G-protein coupled receptor (OTR), which couples to various G-proteins (Gi/o, Gq, Gs) to stimulate diverse signaling pathways. CHO cells expressing marmoset (mOTR), titi monkey (tOTR), macaque (qOTR), or human (hOTR) OT receptors were used to compare AVP and OT analog-induced signaling. Assessment of Gq-mediated increase in intracellular calcium (Ca2+) demonstrated that AVP was less potent than OT analogs at OTRs from species whose endogenous ligand is Leu8-OT (tOTR, qOTR, hOTR), relative to Pro8-OT. Likewise, AVP-induced membrane hyperpolarization was less potent at these same OTRs. Evaluation of (Ca2+)-activated potassium (K+) channels using the inhibitors apamin, paxilline, and TRAM-34 demonstrated that both intermediate and large conductance Ca2+-activated K+ channels contributed to membrane hyperpolarization, with different pharmacological profiles identified for distinct ligand-receptor combinations. Understanding more fully the contributions of structure activity relationships for these peptide ligands at vasopressin and OT receptors will help guide the development of OT-mediated therapeutics.
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U2 - 10.1016/j.biopha.2020.109832
DO - 10.1016/j.biopha.2020.109832
M3 - Article
C2 - 32018219
AN - SCOPUS:85078657664
VL - 125
JO - Biomedicine and Pharmacotherapy
JF - Biomedicine and Pharmacotherapy
SN - 0753-3322
M1 - 109832
ER -