Potent and selective inhibition of angiotensin AT1 receptor signaling by RGS2: roles of its N-terminal domain

Cell Signal. 2011 Jun;23(6):1041-9. doi: 10.1016/j.cellsig.2011.01.023. Epub 2011 Feb 1.


Emerging evidence indicates that R4/B subfamily RGS (regulator of G protein signaling) proteins play roles in functional regulation in the cardiovascular system. In this study, we compared effects of three R4/B subfamily proteins, RGS2, RGS4 and RGS5 on angiotensin AT1 receptor signaling, and investigated roles of the N-terminus of RGS2. In HEK293T cells expressing AT1 receptor stably, intracellular Ca(2+) responses induced by angiotensin II were much more strongly attenuated by RGS2 than by RGS4 and RGS5. N-terminally deleted RGS2 proteins lost this potent inhibitory effect. Replacement of the N-terminal residues 1-71 of RGS2 with the corresponding residues (1-51) of RGS5 decreased significantly the inhibitory effect. On the other hand, replacement of the residues 1-51 of RGS5 with the residues 1-71 of RGS2 increased the inhibitory effect dramatically. Furthermore, we investigated functional contribution of N-terminal subdomains of RGS2, namely, an N-terminal region (residues 16-55) with an amphipathic α helix domain (the subdomain N1), a probable non-specific membrane-targeting subdomain, and another region (residues 56-71) between the α helix and the RGS box (the subdomain N2), a probable GPCR-recognizing subdomain. RGS2 chimera proteins with the residues 1-33 or 34-52 of RGS5 showed weak inhibitory activity, and either of RGS5 chimera proteins with residues 1-55 or 56-71 of RGS2 showed strong inhibitory effects on AT1 receptor signaling. The present study indicates the essential roles of both N-terminal subdomains for the potent inhibitory activity of RGS2 on AT1 receptor signaling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin II / pharmacology
  • Angiotensin II Type 1 Receptor Blockers / metabolism*
  • Animals
  • Calcium / metabolism
  • Endothelin-1 / pharmacology
  • HEK293 Cells
  • Humans
  • Male
  • Mice
  • Muscle, Smooth, Vascular / cytology
  • Muscle, Smooth, Vascular / metabolism
  • Myocardium / metabolism
  • Protein Structure, Tertiary*
  • RGS Proteins / genetics
  • RGS Proteins / metabolism*
  • Rats
  • Receptor, Angiotensin, Type 1 / metabolism*
  • Receptors, Endothelin / metabolism
  • Recombinant Fusion Proteins / metabolism
  • Signal Transduction
  • Transcription, Genetic


  • Angiotensin II Type 1 Receptor Blockers
  • Endothelin-1
  • RGS Proteins
  • RGS2 protein, human
  • Receptor, Angiotensin, Type 1
  • Receptors, Endothelin
  • Recombinant Fusion Proteins
  • Angiotensin II
  • Calcium