Neuregulins regulate cardiac parasympathetic activity: Muscarinic modulation of β-adrenergic activity in myocytes from mice with neuregulin-1 gene deletion

Katashi Okoshi, Masaharu Nakayama, Xinhua Yan, Marina P. Okoshi, Adam J.T. Schuldt, Mark A. Marchionni, Beverly H. Lorell

Research output: Contribution to journalArticlepeer-review

54 Citations (Scopus)

Abstract

Background-Neuregulins are required for maintenance of acetylcholine receptor-inducing activity of nicotinic receptors in neurons and skeletal muscle, but effects of neuregulins on muscarinic receptors are not known. In the normal heart, parasympathetic activation counterbalances β-adrenergic activation. To test the hypothesis that neuregulins modify parasympathetic function in the heart, we studied cardiomyocytes from mice heterozygous for neuregulin-1 gene deletion (NRG-1+/-) and examined the effects of β-adrenergic stimulation on contractility in the presence and absence of the muscarinic agonist carbachol. Methods and Results-We evaluated contraction and intracellular Ca2+ transients ([Ca2+]i) in left ventricular (LV) myocytes loaded with Fluo-3 from NRG-1+/- and wild-type (WT) mice. Under baseline conditions (0.5 Hz, 1.5 mmol/L [Ca 2+]o, 25°C), characteristics of myocyte contraction/relengthening and systolic/diastolic [Ca2+]i were not different between WT and NRG-1+/- mice. The steady-state increases in fractional shortening (FS) and peak-systolic [Ca2+] i in response to isoproterenol were similar in both groups. In WT myocytes stimulated with isoproterenol, carbachol decreased FS, peak-systolic [Ca2+]i, and cAMP levels. In NRG-1+/- myocytes, carbachol did not attenuate either FS or peak-systolic [Ca2+] i, associated with the failure to decrease cAMP levels. Investigation of muscarinic receptor signaling showed no difference of LV protein levels of muscarinic M2 receptors or G protein Gαi1,2, Gαi3, and Gαo subunits. Conclusions- Cardiomyocytes deficient in neuregulin signaling are unable to adequately counterbalance β-adrenergic activation by inhibitory parasympathetic activity. This mechanism may contribute to the known increased risk of heart failure in injured human hearts when neuregulin signaling is suppressed.

Original languageEnglish
Pages (from-to)713-717
Number of pages5
JournalCirculation
Volume110
Issue number6
DOIs
Publication statusPublished - 2004 Aug 10
Externally publishedYes

Keywords

  • Acetylcholine
  • Calcium
  • Contractility
  • Myocytes
  • Neuregulins

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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