Neuregulins regulate cardiac parasympathetic activity: muscarinic modulation of beta-adrenergic activity in myocytes from mice with neuregulin-1 gene deletion.
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 beta-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 beta-adrenergic stimulation on contractility in the presence and absence of the muscarinic agonist carbachol.


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 [Ca2+]o, 25 degrees 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 Galpha(i1,2), Galpha(i3), and Galpha(o) subunits.


CONCLUSIONS
Cardiomyocytes deficient in neuregulin signaling are unable to adequately counterbalance beta-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.
Okoshi
Katashi
K
Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Mass 02215, USA.
Nakayama
Masaharu
M
Yan
Xinhua
X
Okoshi
Marina P
MP
Schuldt
Adam J T
AJ
Marchionni
Mark A
MA
Lorell
Beverly H
BH
D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects; D002217:Carbachol / Q000494:pharmacology; D002478:Cells, Cultured / Q000187:drug effects / Q000502:physiology; D000242:Cyclic AMP / Q000502:physiology; D017353:Gene Deletion; D006329:Heart Conduction System / Q000187:drug effects / Q000502:physiology; D006579:Heterozygote; D007545:Isoproterenol / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D018721:Muscarinic Agonists / Q000494:pharmacology; D009200:Myocardial Contraction / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology; D020890:Neuregulin-1 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D010275:Parasympathetic Nervous System / Q000187:drug effects / Q000502:physiology; D043585:Receptor, Muscarinic M2 / Q000502:physiology*; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000502:physiology
D000318:Adrenergic beta-Agonists; C495964:Chrnb1 protein, mouse; D018721:Muscarinic Agonists; D020890:Neuregulin-1; D043585:Receptor, Muscarinic M2; D011978:Receptors, Nicotinic; D002217:Carbachol; D000242:Cyclic AMP; D007545:Isoproterenol