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http://purl.uniprot.org/citations/15289373http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/15289373http://www.w3.org/2000/01/rdf-schema#comment"

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.

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 [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."xsd:string
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http://purl.uniprot.org/citations/15289373http://purl.uniprot.org/core/author"Nakayama M."xsd:string
http://purl.uniprot.org/citations/15289373http://purl.uniprot.org/core/author"Yan X."xsd:string
http://purl.uniprot.org/citations/15289373http://purl.uniprot.org/core/author"Marchionni M.A."xsd:string
http://purl.uniprot.org/citations/15289373http://purl.uniprot.org/core/author"Okoshi K."xsd:string
http://purl.uniprot.org/citations/15289373http://purl.uniprot.org/core/author"Lorell B.H."xsd:string
http://purl.uniprot.org/citations/15289373http://purl.uniprot.org/core/author"Schuldt A.J."xsd:string
http://purl.uniprot.org/citations/15289373http://purl.uniprot.org/core/author"Okoshi M.P."xsd:string
http://purl.uniprot.org/citations/15289373http://purl.uniprot.org/core/date"2004"xsd:gYear
http://purl.uniprot.org/citations/15289373http://purl.uniprot.org/core/name"Circulation"xsd:string
http://purl.uniprot.org/citations/15289373http://purl.uniprot.org/core/pages"713-717"xsd:string
http://purl.uniprot.org/citations/15289373http://purl.uniprot.org/core/title"Neuregulins regulate cardiac parasympathetic activity: muscarinic modulation of beta-adrenergic activity in myocytes from mice with neuregulin-1 gene deletion."xsd:string
http://purl.uniprot.org/citations/15289373http://purl.uniprot.org/core/volume"110"xsd:string
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