V1b and CRHR1 receptor heterodimerization mediates synergistic biological actions of vasopressin and CRH

Mol Endocrinol. 2012 Mar;26(3):502-20. doi: 10.1210/me.2011-1202. Epub 2012 Feb 2.


Vasopressin (AVP) and CRH synergistically regulate adrenocorticotropin and insulin release at the level of the pituitary and pancreas, respectively. Here, we first extended these AVP and CRH coregulation processes to the adrenal medulla. We demonstrate that costimulation of chromaffin cells by AVP and CRH simultaneously induces a catecholamine secretion exceeding the one induced by each hormone alone, thus demonstrating a net potentiation. To further elucidate the molecular mechanisms underlying this synergism, we coexpressed human V1b and CRH receptor (CRHR)1 receptor in HEK293 cells. In this heterologous system, AVP also potentiated CRH-stimulated cAMP accumulation in a dose-dependent and saturable manner. This effect was only partially mimicked by phorbol ester or inhibited by a phospholipase C inhibitor respectively. This finding suggests the existence of an new molecular mechanism, independent from second messenger cross talk. Similarly, CRH potentiated the AVP-induced inositol phosphates production. Using bioluminescence resonance energy transfer, coimmunoprecipitation, and receptor rescue experiments, we demonstrate that V1b and CRHR1 receptors assemble as heterodimers. Moreover, new pharmacological properties emerged upon receptors cotransfection. Taken together, these data strongly suggest that direct molecular interactions between V1b and CRHR1 receptors play an important role in mediating the synergistic interactions between these two receptors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenal Glands / cytology
  • Animals
  • Antidiuretic Hormone Receptor Antagonists
  • Catecholamines / metabolism
  • Cattle
  • Cells, Cultured
  • Chromaffin Cells / metabolism
  • Corticotropin-Releasing Hormone / pharmacology
  • Corticotropin-Releasing Hormone / physiology*
  • Cyclic AMP / metabolism
  • Enzyme Activation
  • Estrenes / pharmacology
  • HEK293 Cells
  • Humans
  • Hydrocarbons, Halogenated / pharmacology
  • Indoles / pharmacology
  • Inositol Polyphosphate 5-Phosphatases
  • Phosphoric Monoester Hydrolases / metabolism
  • Primary Cell Culture
  • Protein Binding
  • Protein Multimerization*
  • Pyrrolidines / pharmacology
  • Pyrrolidinones / pharmacology
  • Receptor Cross-Talk
  • Receptors, Corticotropin-Releasing Hormone / agonists
  • Receptors, Corticotropin-Releasing Hormone / antagonists & inhibitors
  • Receptors, Corticotropin-Releasing Hormone / metabolism*
  • Receptors, Vasopressin / agonists
  • Receptors, Vasopressin / metabolism*
  • Recombinant Fusion Proteins / agonists
  • Recombinant Fusion Proteins / metabolism
  • Second Messenger Systems
  • Thiazines / pharmacology
  • Type C Phospholipases / antagonists & inhibitors
  • Type C Phospholipases / metabolism
  • Vasopressins / pharmacology
  • Vasopressins / physiology*


  • 1-(5-chloro-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl)-4-hydroxy-N,N-dimethyl-2-pyrrolidinecarboxamide
  • Antidiuretic Hormone Receptor Antagonists
  • Catecholamines
  • Estrenes
  • Hydrocarbons, Halogenated
  • Indoles
  • Pyrrolidines
  • Pyrrolidinones
  • Receptors, Corticotropin-Releasing Hormone
  • Receptors, Vasopressin
  • Recombinant Fusion Proteins
  • SSR125543
  • Thiazines
  • Vasopressins
  • 1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione
  • CRF receptor type 1
  • Corticotropin-Releasing Hormone
  • Cyclic AMP
  • Phosphoric Monoester Hydrolases
  • Inositol Polyphosphate 5-Phosphatases
  • Type C Phospholipases