Extracellular loop 3 (ECL3) and ECL3-proximal transmembrane domains VI and VII of the mesotocin and vasotocin receptors confer differential ligand selectivity and signaling activity

Hyun Ju Cho, Mi Jin Moon, Hyuk Bang Kwon, Jong-Ik Hwang, Jae Young Seong

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Mesotocin (MT) and vasotocin (VT) are the nonmammalian orthologs of mammalian oxytocin (OT) and arginine vasopressin (AVP), respectively. The OT/AVP family of peptides has arisen from gene duplication but has evolved to possess high selectivity toward their cognate receptors. The process of molecular evolution of receptors to confer high selectivity to their cognate ligands, however, is poorly understood. We constructed a series of reciprocal chimeras using a pair of bullfrog MT receptor (MTR) and VT1 receptor (VT1R) DNA fragments. Among the MTR/VT1R chimeras, the MTR chimera containing a region from transmembrane domain (TMD) VI to the carboxyl-terminal tail (C-tail) of VT1R showed an increased sensitivity to VT, while a chimeric VT1R containing TMD VI to C-tail of MTR showed an increased sensitivity to MT. Further dissection of domains using additional chimeras demonstrated that the receptor with the fragment containing extracellular loop 3 (ECL3) and ECL3-proximal TMDs VI and VII of MTR increased MT selectivity. This fragment is also important for receptor conformation that permits the signaling ability of the receptor. Particularly, the amino acids Val/Ile 6.54 in TMD VI and Pro/Glu 7.29 in ECL3 appear to be involved in this activity, since double mutation of these amino acids completely blocked signaling activity while maintaining ligand binding activity. Mutations at these residues in human OT and AVP 1a receptors markedly decreased receptor signaling activity. This study provides clues for understanding molecular coevolution of the OT/AVP peptides and their receptors with regard to receptor-ligand binding and receptor signaling activity.

Original languageEnglish
Pages (from-to)71-82
Number of pages12
JournalGeneral and Comparative Endocrinology
Volume156
Issue number1
DOIs
Publication statusPublished - 2008 Mar 1

Fingerprint

Oxytocin
Arginine Vasopressin
Ligands
Vasotocin
Tail
Amino Acids
Rana catesbeiana
Mutation
Gene Duplication
Peptide Receptors
Molecular Evolution
Dissection
mesotocin receptor
vasotocin receptor
Peptides
DNA
mesotocin

Keywords

  • Arginine vasopressin
  • Extracellular loop
  • Ligand selectivity
  • Mesotocin
  • Oxytocin
  • Receptor
  • Transmembrane domain
  • Vasotocin

ASJC Scopus subject areas

  • Endocrinology

Cite this

@article{2aa505557843418095968cb42a49e17e,
title = "Extracellular loop 3 (ECL3) and ECL3-proximal transmembrane domains VI and VII of the mesotocin and vasotocin receptors confer differential ligand selectivity and signaling activity",
abstract = "Mesotocin (MT) and vasotocin (VT) are the nonmammalian orthologs of mammalian oxytocin (OT) and arginine vasopressin (AVP), respectively. The OT/AVP family of peptides has arisen from gene duplication but has evolved to possess high selectivity toward their cognate receptors. The process of molecular evolution of receptors to confer high selectivity to their cognate ligands, however, is poorly understood. We constructed a series of reciprocal chimeras using a pair of bullfrog MT receptor (MTR) and VT1 receptor (VT1R) DNA fragments. Among the MTR/VT1R chimeras, the MTR chimera containing a region from transmembrane domain (TMD) VI to the carboxyl-terminal tail (C-tail) of VT1R showed an increased sensitivity to VT, while a chimeric VT1R containing TMD VI to C-tail of MTR showed an increased sensitivity to MT. Further dissection of domains using additional chimeras demonstrated that the receptor with the fragment containing extracellular loop 3 (ECL3) and ECL3-proximal TMDs VI and VII of MTR increased MT selectivity. This fragment is also important for receptor conformation that permits the signaling ability of the receptor. Particularly, the amino acids Val/Ile 6.54 in TMD VI and Pro/Glu 7.29 in ECL3 appear to be involved in this activity, since double mutation of these amino acids completely blocked signaling activity while maintaining ligand binding activity. Mutations at these residues in human OT and AVP 1a receptors markedly decreased receptor signaling activity. This study provides clues for understanding molecular coevolution of the OT/AVP peptides and their receptors with regard to receptor-ligand binding and receptor signaling activity.",
keywords = "Arginine vasopressin, Extracellular loop, Ligand selectivity, Mesotocin, Oxytocin, Receptor, Transmembrane domain, Vasotocin",
author = "Cho, {Hyun Ju} and Moon, {Mi Jin} and Kwon, {Hyuk Bang} and Jong-Ik Hwang and Seong, {Jae Young}",
year = "2008",
month = "3",
day = "1",
doi = "10.1016/j.ygcen.2007.11.010",
language = "English",
volume = "156",
pages = "71--82",
journal = "General and Comparative Endocrinology",
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T1 - Extracellular loop 3 (ECL3) and ECL3-proximal transmembrane domains VI and VII of the mesotocin and vasotocin receptors confer differential ligand selectivity and signaling activity

AU - Cho, Hyun Ju

AU - Moon, Mi Jin

AU - Kwon, Hyuk Bang

AU - Hwang, Jong-Ik

AU - Seong, Jae Young

PY - 2008/3/1

Y1 - 2008/3/1

N2 - Mesotocin (MT) and vasotocin (VT) are the nonmammalian orthologs of mammalian oxytocin (OT) and arginine vasopressin (AVP), respectively. The OT/AVP family of peptides has arisen from gene duplication but has evolved to possess high selectivity toward their cognate receptors. The process of molecular evolution of receptors to confer high selectivity to their cognate ligands, however, is poorly understood. We constructed a series of reciprocal chimeras using a pair of bullfrog MT receptor (MTR) and VT1 receptor (VT1R) DNA fragments. Among the MTR/VT1R chimeras, the MTR chimera containing a region from transmembrane domain (TMD) VI to the carboxyl-terminal tail (C-tail) of VT1R showed an increased sensitivity to VT, while a chimeric VT1R containing TMD VI to C-tail of MTR showed an increased sensitivity to MT. Further dissection of domains using additional chimeras demonstrated that the receptor with the fragment containing extracellular loop 3 (ECL3) and ECL3-proximal TMDs VI and VII of MTR increased MT selectivity. This fragment is also important for receptor conformation that permits the signaling ability of the receptor. Particularly, the amino acids Val/Ile 6.54 in TMD VI and Pro/Glu 7.29 in ECL3 appear to be involved in this activity, since double mutation of these amino acids completely blocked signaling activity while maintaining ligand binding activity. Mutations at these residues in human OT and AVP 1a receptors markedly decreased receptor signaling activity. This study provides clues for understanding molecular coevolution of the OT/AVP peptides and their receptors with regard to receptor-ligand binding and receptor signaling activity.

AB - Mesotocin (MT) and vasotocin (VT) are the nonmammalian orthologs of mammalian oxytocin (OT) and arginine vasopressin (AVP), respectively. The OT/AVP family of peptides has arisen from gene duplication but has evolved to possess high selectivity toward their cognate receptors. The process of molecular evolution of receptors to confer high selectivity to their cognate ligands, however, is poorly understood. We constructed a series of reciprocal chimeras using a pair of bullfrog MT receptor (MTR) and VT1 receptor (VT1R) DNA fragments. Among the MTR/VT1R chimeras, the MTR chimera containing a region from transmembrane domain (TMD) VI to the carboxyl-terminal tail (C-tail) of VT1R showed an increased sensitivity to VT, while a chimeric VT1R containing TMD VI to C-tail of MTR showed an increased sensitivity to MT. Further dissection of domains using additional chimeras demonstrated that the receptor with the fragment containing extracellular loop 3 (ECL3) and ECL3-proximal TMDs VI and VII of MTR increased MT selectivity. This fragment is also important for receptor conformation that permits the signaling ability of the receptor. Particularly, the amino acids Val/Ile 6.54 in TMD VI and Pro/Glu 7.29 in ECL3 appear to be involved in this activity, since double mutation of these amino acids completely blocked signaling activity while maintaining ligand binding activity. Mutations at these residues in human OT and AVP 1a receptors markedly decreased receptor signaling activity. This study provides clues for understanding molecular coevolution of the OT/AVP peptides and their receptors with regard to receptor-ligand binding and receptor signaling activity.

KW - Arginine vasopressin

KW - Extracellular loop

KW - Ligand selectivity

KW - Mesotocin

KW - Oxytocin

KW - Receptor

KW - Transmembrane domain

KW - Vasotocin

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U2 - 10.1016/j.ygcen.2007.11.010

DO - 10.1016/j.ygcen.2007.11.010

M3 - Article

VL - 156

SP - 71

EP - 82

JO - General and Comparative Endocrinology

JF - General and Comparative Endocrinology

SN - 0016-6480

IS - 1

ER -