Agonist-induced internalization of histamine H2 receptor and activation of extracellular signal-regulated kinases are dynamin-dependent

J Neurochem. 2008 Oct;107(1):208-17. doi: 10.1111/j.1471-4159.2008.05608.x. Epub 2008 Aug 7.

Abstract

Histamine H2 receptor (H2R) is a member of G protein-coupled receptor family. Agonist stimulation of H2R results in several cellular events including activation of adenylate cyclase and phospholipase C, desensitization of the receptor, activation of extracellular signal-regulated kinases ERK1/2, and receptor endocytosis. In this study, we identified a GTPase dynamin as a binding partner of H2R. Dynamin could associate with H2R both in vitro and in vivo. Functional analyses using dominant-negative form of dynamin (K44E-dynamin) revealed that cAMP production and the following H2R desensitization are independent of dynamin. However, the agonist-induced H2R internalization was inhibited by co-expression of K44E-dynamin. Furthermore, activation of extracellular-signal regulated kinases ERK1/2 in response to dimaprit, an H2R agonist, was attenuated by K44E-dynamin. Although H2R with truncation of 51 amino acids at its carboxy-terminus did not internalize after agonist stimulation, it still activated ERK1/2, but the degree of this activation was less than that of the wild-type receptor. Finally, K44E dynamin did not affect ERK1/2 activation induced by internalization-deficient H2R. These results suggest that the agonist-induced H2R internalization and ERK1/2 activation are partially dynamin-dependent. Furthermore, ERK1/2 activation via H2R is likely dependent of the endocytotic process rather than dynamin itself.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • COS Cells
  • Chlorocebus aethiops
  • Cyclic AMP / biosynthesis
  • Dimaprit / pharmacology
  • Dynamins / metabolism*
  • Endocytosis / drug effects
  • Endocytosis / physiology*
  • Enzyme Activation / drug effects
  • Enzyme Activation / physiology
  • Extracellular Signal-Regulated MAP Kinases / drug effects
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • Histamine Agonists / pharmacology*
  • Humans
  • Mitogen-Activated Protein Kinase 1 / drug effects
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / drug effects
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Protein Structure, Tertiary / physiology
  • Protein Transport / drug effects
  • Protein Transport / physiology
  • Receptors, Histamine H2 / chemistry
  • Receptors, Histamine H2 / drug effects*
  • Receptors, Histamine H2 / metabolism*
  • Signal Transduction / drug effects
  • Signal Transduction / physiology

Substances

  • Histamine Agonists
  • Receptors, Histamine H2
  • Cyclic AMP
  • Extracellular Signal-Regulated MAP Kinases
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Dynamins
  • Dimaprit