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Overexpression of wild‐type Gαi‐2 suppresses β‐adrenergic signaling in cardiac myocytes
Author(s) -
Rau Thomas,
Nose Monika,
Remmers Ute,
Weil Joachim,
Weiβmüller Astrid,
Davia Kerry,
Harding Sian,
Peppel Karsten,
Koch Walter J.,
Eschenhagen Thomas
Publication year - 2003
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.02-0660fje
Subject(s) - isoprenaline , medicine , stimulation , myocyte , endocrinology , gs alpha subunit , adenylyl cyclase , g protein , heart failure , biology , receptor
The role of Gαi‐2 overexpression in desensitization of β‐adrenergic signaling in heart failure is controversial. An adenovirus‐based approach was used to investigate whether overexpression of Gαi‐2 impairs β‐adrenergic stimulation of adenylyl cyclase (AC) activity and cAMP levels in neonatal rat cardiac myocytes (NRCM) and cell shortening of adult rat ventricular myocytes (ARVM). Infection of NRCM with Ad5Gαi‐2 increased Gαi‐2 by 50–600% in a virus dose‐dependent manner. Overexpression was paralleled by suppression of GTP‐ and isoprenaline‐stimulated AC by 10–72% ( P <0.001) in a PTX‐sensitive manner. Isoprenaline‐stimulated shortening of Ad5Gαi‐2‐infected ARVM was attenuated by 34% ( P <0.01). Ad5Gαi‐2/GFP (Gαi‐2, green fluorescent protein; bicistronic) was constructed to monitor transfection homogeneity and target Gαi‐2 overexpression to levels found in heart failure. At Gαi‐2 levels of 93% above control, isoprenaline‐stimulated AC activity and cAMP levels were reduced by 17% and 40% ( P <0.02), respectively. β1‐ and β2‐adrenergic stimulation was reduced similarly. Our results suggest that (a) the Gαi‐2 system exhibits tonic inhibition of stimulated AC in cardiac myocytes, (b) Gαi‐2‐mediated inhibition is concentration‐dependent and occurs at Gαi‐2 levels seen in heart failure, and (c) Gαi‐2‐mediated inhibition affects both β1‐ and β2‐adrenergic stimulation of AC. The data argue for an important, independent role of the Gαi‐2 increase in heart failure.