Scholars@Duke publication: Age increases cardiac Galpha(i2) expression, resulting in enhanced coupling to G protein-coupled receptors.

Age increases cardiac Galpha(i2) expression, resulting in enhanced coupling to G protein-coupled receptors.

Publication , Journal Article

Kilts, JD; Akazawa, T; Richardson, MD; Kwatra, MM

Published in: J Biol Chem

August 23, 2002

Cardiac G protein-coupled receptors that function through stimulatory G protein Galpha(s), such as beta(1)- and beta(2)-adrenergic receptors (beta(1)ARs and beta(2)ARs), play a key role in cardiac contractility. Recent data indicate that several Galpha(s)-coupled receptors in heart also activate Galpha(i), including beta(2)ARs (but not beta(1)ARs). Coupling of cardiac beta(2)ARs to Galpha(i) inhibits adenylyl cyclase and opposes beta(1)AR-mediated apoptosis. Dual coupling of beta(2)AR to both Galpha(s) and Galpha(i) is likely to alter beta(2)AR function in disease, such as congestive heart failure in which Galpha(i) levels are increased. Indeed, heart failure is characterized by reduced responsiveness of betaARs. Cardiac betaAR-responsiveness is also decreased with aging. However, whether age increases cardiac Galpha(i) has been controversial, with some studies reporting an increase and others reporting no change. The present study examines Galpha(i) in left ventricular membranes from young and old Fisher 344 rats by employing a comprehensive battery of biochemical assays. Immunoblotting reveals significant increases with age in left ventricular Galpha(i2), but no changes in Galpha(i3), Galpha(o), Galpha(s), Gbeta(1), or Gbeta(2). Aging also increases ADP-ribosylation of pertussis toxin-sensitive G proteins. Consistent with these results, basal as well as receptor-mediated incorporation of photoaffinity label [(32)P]azidoanilido-GTP indicates higher amounts of Galpha(i2) in older left ventricular membranes. Moreover, both basal and receptor-mediated adenylyl cyclase activities are lower in left ventricular membranes from older rats, and disabling of Galpha(i) with pertussis toxin increases both basal and receptor-stimulated adenylyl cyclase activity. Finally, age produces small but significant increases in muscarinic potency for the inhibition of both beta(1)AR- and beta(2)AR-stimulated adenylyl cyclase activity. The present study establishes that Galpha(i2) increases with age and provides data indicating that this increase dampens adenylyl cyclase activity.

Duke Scholars

Author Jason David Kilts Psychiatry, Child & Family Mental Health & Community Psychia ...

Author Madan Mohan Kwatra Anesthesiology

Published In

J Biol Chem

DOI

10.1074/jbc.M203640200

ISSN

0021-9258

Publication Date

August 23, 2002

Volume

277

Issue

Start / End Page

31257 / 31262

Location

United States

Related Subject Headings

Virulence Factors, Bordetella
Receptors, Adrenergic, beta-2
Receptors, Adrenergic, beta-1
Rats, Inbred F344
Rats
Proto-Oncogene Proteins
Pertussis Toxin
Myocardium
GTP-Binding Protein alpha Subunits, Gi-Go
GTP-Binding Protein alpha Subunit, Gi2

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Kilts, J. D., Akazawa, T., Richardson, M. D., & Kwatra, M. M. (2002). Age increases cardiac Galpha(i2) expression, resulting in enhanced coupling to G protein-coupled receptors. J Biol Chem, 277(34), 31257–31262. https://doi.org/10.1074/jbc.M203640200

Kilts, Jason D., Toshimasa Akazawa, Mark D. Richardson, and Madan M. Kwatra. “Age increases cardiac Galpha(i2) expression, resulting in enhanced coupling to G protein-coupled receptors.” J Biol Chem 277, no. 34 (August 23, 2002): 31257–62. https://doi.org/10.1074/jbc.M203640200.

Kilts JD, Akazawa T, Richardson MD, Kwatra MM. Age increases cardiac Galpha(i2) expression, resulting in enhanced coupling to G protein-coupled receptors. J Biol Chem. 2002 Aug 23;277(34):31257–62.

Kilts, Jason D., et al. “Age increases cardiac Galpha(i2) expression, resulting in enhanced coupling to G protein-coupled receptors.” J Biol Chem, vol. 277, no. 34, Aug. 2002, pp. 31257–62. Pubmed, doi:10.1074/jbc.M203640200.

Kilts JD, Akazawa T, Richardson MD, Kwatra MM. Age increases cardiac Galpha(i2) expression, resulting in enhanced coupling to G protein-coupled receptors. J Biol Chem. 2002 Aug 23;277(34):31257–31262.