Heteromerization of G2A and OGR1 enhances proton sensitivity and proton-induced calcium signals

J Recept Signal Transduct Res. 2016 Dec;36(6):633-644. doi: 10.3109/10799893.2016.1155064. Epub 2016 Apr 6.

Abstract

Proton-sensing G-protein-coupled receptors (GPCRs; OGR1, GPR4, G2A, TDAG8), with full activation at pH 6.4 ∼ 6.8, are important to pH homeostasis, immune responses and acid-induced pain. Although G2A mediates the G13-Rho pathway in response to acid, whether G2A activates Gs, Gi or Gq proteins remains debated. In this study, we examined the response of this fluorescence protein-tagged OGR1 family to acid stimulation in HEK293T cells. G2A did not generate detectable intracellular calcium or cAMP signals or show apparent receptor redistribution with moderate acid (pH ≥ 6.0) stimulation but reduced cAMP accumulation under strong acid stimulation (pH ≤ 5.5). Surprisingly, coexpression of OGR1- and G2A-enhanced proton sensitivity and proton-induced calcium signals. This alteration is attributed to oligomerization of OGR1 and G2A. The oligomeric potential locates receptors at a specific site, which leads to enhanced proton-induced calcium signals through channels.

Keywords: G-protein signaling; G2A; OGR1; Proton-sensing G protein-coupled receptor; heteromerization.

MeSH terms

  • Acids / chemistry
  • Calcium / metabolism
  • Calcium Signaling / genetics*
  • Cell Cycle Proteins / chemistry*
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism
  • Cyclic AMP / chemistry
  • Gene Expression Regulation
  • HEK293 Cells
  • Humans
  • Hydrogen-Ion Concentration
  • Protein Multimerization
  • Protons*
  • Receptors, G-Protein-Coupled / chemistry*
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism

Substances

  • Acids
  • Cell Cycle Proteins
  • G2A receptor
  • GPR68 protein, human
  • Protons
  • Receptors, G-Protein-Coupled
  • Cyclic AMP
  • Calcium