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Beta-arrestin2-mediated inotropic effects of the angiotensin II type 1A receptor in isolated cardiac myocytes.

Publication ,  Journal Article
Rajagopal, K; Whalen, EJ; Violin, JD; Stiber, JA; Rosenberg, PB; Premont, RT; Coffman, TM; Rockman, HA; Lefkowitz, RJ
Published in: Proc Natl Acad Sci U S A
October 31, 2006

The G protein-coupled receptor kinases (GRKs) and beta-arrestins, families of molecules essential to the desensitization of G protein-dependent signaling via seven-transmembrane receptors (7TMRs), have been recently shown to also transduce G protein-independent signals from receptors. However, the physiologic consequences of this G protein-independent, GRK/beta-arrestin-dependent signaling are largely unknown. Here, we establish that GRK/beta-arrestin-mediated signal transduction via the angiotensin II (ANG) type 1A receptor (AT(1A)R) results in positive inotropic and lusitropic effects in isolated adult mouse cardiomyocytes. We used the "biased" AT(1A)R agonist [Sar(1), Ile(4), Ile(8)]-angiotensin II (SII), which is unable to stimulate G(alpha)q-mediated signaling, but which has previously been shown to promote beta-arrestin interaction with the AT(1A)R. Cardiomyocytes from WT, but not AT(1A)R-deficient knockout (KO) mice, exhibited positive inotropic and lusitropic responses to both ANG and SII. Responses of WT cardiomyocytes to ANG were dramatically reduced by protein kinase C (PKC) inhibition, whereas those to SII were unaffected. In contrast, cardiomyocytes from beta-arrestin2 KO and GRK6 KO mice failed to respond to SII, but displayed preserved responses to ANG. Cardiomyocytes from GRK2 heterozygous knockout mice (GRK2(+/-)) exhibited augmented responses to SII in comparison to ANG, whereas those from GRK5 KO mice did not differ from those from WT mice. These findings indicate the existence of independent G(alpha)q/PKC- and GRK6/beta-arrestin2-dependent mechanisms by which stimulation of the AT(1A)R can modulate cardiomyocyte function, and which can be differentially activated by selective receptor ligands. Such ligands may have potential as a novel class of therapeutic agents.

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Published In

Proc Natl Acad Sci U S A

DOI

ISSN

0027-8424

Publication Date

October 31, 2006

Volume

103

Issue

44

Start / End Page

16284 / 16289

Location

United States

Related Subject Headings

  • beta-Arrestins
  • Signal Transduction
  • Receptor, Angiotensin, Type 1
  • Protein Kinase C
  • Myocytes, Cardiac
  • Mice, Inbred C57BL
  • Mice
  • Male
  • Isoenzymes
  • Humans
 

Citation

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Rajagopal, K., Whalen, E. J., Violin, J. D., Stiber, J. A., Rosenberg, P. B., Premont, R. T., … Lefkowitz, R. J. (2006). Beta-arrestin2-mediated inotropic effects of the angiotensin II type 1A receptor in isolated cardiac myocytes. Proc Natl Acad Sci U S A, 103(44), 16284–16289. https://doi.org/10.1073/pnas.0607583103
Rajagopal, Keshava, Erin J. Whalen, Jonathan D. Violin, Jonathan A. Stiber, Paul B. Rosenberg, Richard T. Premont, Thomas M. Coffman, Howard A. Rockman, and Robert J. Lefkowitz. “Beta-arrestin2-mediated inotropic effects of the angiotensin II type 1A receptor in isolated cardiac myocytes.Proc Natl Acad Sci U S A 103, no. 44 (October 31, 2006): 16284–89. https://doi.org/10.1073/pnas.0607583103.
Rajagopal K, Whalen EJ, Violin JD, Stiber JA, Rosenberg PB, Premont RT, et al. Beta-arrestin2-mediated inotropic effects of the angiotensin II type 1A receptor in isolated cardiac myocytes. Proc Natl Acad Sci U S A. 2006 Oct 31;103(44):16284–9.
Rajagopal, Keshava, et al. “Beta-arrestin2-mediated inotropic effects of the angiotensin II type 1A receptor in isolated cardiac myocytes.Proc Natl Acad Sci U S A, vol. 103, no. 44, Oct. 2006, pp. 16284–89. Pubmed, doi:10.1073/pnas.0607583103.
Rajagopal K, Whalen EJ, Violin JD, Stiber JA, Rosenberg PB, Premont RT, Coffman TM, Rockman HA, Lefkowitz RJ. Beta-arrestin2-mediated inotropic effects of the angiotensin II type 1A receptor in isolated cardiac myocytes. Proc Natl Acad Sci U S A. 2006 Oct 31;103(44):16284–16289.
Journal cover image

Published In

Proc Natl Acad Sci U S A

DOI

ISSN

0027-8424

Publication Date

October 31, 2006

Volume

103

Issue

44

Start / End Page

16284 / 16289

Location

United States

Related Subject Headings

  • beta-Arrestins
  • Signal Transduction
  • Receptor, Angiotensin, Type 1
  • Protein Kinase C
  • Myocytes, Cardiac
  • Mice, Inbred C57BL
  • Mice
  • Male
  • Isoenzymes
  • Humans