Bi-directional heterologous desensitization between the major HIV-1 co-receptor CXCR4 and the kappa-opioid receptor

J Neuroimmunol. 2008 Jul 15;197(2):114-23. doi: 10.1016/j.jneuroim.2008.04.021. Epub 2008 Jun 3.

Abstract

We previously characterized multiple interactions between chemokine and opioid G protein-coupled receptors (GPCR), and we found both mu and delta-opioid receptors cross-desensitize CCR1, CCR2, CCR5, but not CXCR4. Here we report that the kappa-opioid receptor (KOR) is able to cross-desensitize CXCR4, and this phenomenon is bi-directional. Chemotactic responses by KOR activation are diminished with prior activation of CXCR4. Additionally, calcium mobilization assays show these cross-desensitization processes occur within seconds of receptor activation, and target receptor internalization is not responsible for desensitization between these receptors. These results have implications for several essential processes including neuronal and lymphocyte development, inflammatory responses, and pain/sensitivity.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / pharmacology
  • Analgesics, Non-Narcotic / pharmacology
  • Analysis of Variance
  • Animals
  • Calcium / metabolism
  • Chemokine CXCL12 / pharmacology
  • Chemotaxis / drug effects
  • Chemotaxis / physiology
  • Dose-Response Relationship, Drug
  • Dynorphins / metabolism
  • Flow Cytometry / methods
  • Gene Expression / drug effects
  • Gene Expression / physiology
  • Gene Expression Regulation / drug effects
  • HIV-1 / physiology*
  • Humans
  • Neutrophils / drug effects
  • Neutrophils / physiology
  • Periaqueductal Gray / drug effects
  • Periaqueductal Gray / metabolism
  • Protein Transport / drug effects
  • Rats
  • Receptors, CXCR4 / genetics
  • Receptors, CXCR4 / metabolism*
  • Receptors, Opioid, kappa / genetics
  • Receptors, Opioid, kappa / metabolism*
  • Time Factors
  • Transfection / methods

Substances

  • Analgesics, Non-Narcotic
  • CXCR4 protein, human
  • Chemokine CXCL12
  • Receptors, CXCR4
  • Receptors, Opioid, kappa
  • 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer
  • Dynorphins
  • Calcium