title: Sarcolemmal α2-adrenoceptors control protective cardiomyocyte-delimited sympathoadrenal response.
abstract: Sustained cardiac adrenergic stimulation has been implicated in the development of heart failure and ventricular dysrhythmia. Conventionally, α2 adrenoceptors (α2-AR) have been assigned to a sympathetic short-loop feedback aimed at attenuating catecholamine release. We have recently revealed the expression of α2-AR in the sarcolemma of cardiomyocytes and identified the ability of α2-AR signaling to suppress spontaneous Ca2+transients through nitric oxide (NO) dependent pathways. Herein, patch-clamp measurements and serine/threonine phosphatase assay revealed that, in isolated rat cardiomyocytes, activation of α2-AR suppressed L-type Ca2+current (ICaL) via stimulation of NO synthesis and protein kinase G- (PKG) dependent activation of phosphatase reactions, counteracting isoproterenol-induced β-adrenergic activation. Under stimulation with norepinephrine (NE), an agonist of β- and α-adrenoceptors, the α2-AR antagonist yohimbine substantially elevated ICaLat NE levels >10nM. Concomitantly, yohimbine potentiated triggered intracellular Ca2+dynamics and contractility of cardiac papillary muscles. Therefore, in addition to the α2-AR-mediated feedback suppression of sympathetic and adrenal catecholamine release, α2-AR in cardiomyocytes can govern a previously unrecognized local cardiomyocyte-delimited stress-reactive signaling pathway. We suggest that such aberrant α2-AR signaling may contribute to the development of cardiomyopathy under sustained sympathetic drive. Indeed, in cardiomyocytes of spontaneously hypertensive rats (SHR), an established model of cardiac hypertrophy, α2-AR signaling was dramatically reduced despite increased α2-AR mRNA levels compared to normal cardiomyocytes. Thus, targeting α2-AR signaling mechanisms in cardiomyocytes may find implications in medical strategies against maladaptive cardiac remodeling associated with chronic sympathoadrenal stimulation.
authors.affiliation: Institute of Theoretical and Experimental Biophysics, Russian Academy of Science, Institutskaya 3, Pushchino, Moscow Region 142290, Russia. Electronic address: yuryikokoz@gmail.com.
authors.forename: Yuri M
authors.initials: YM
authors.lastname: Kokoz
authors.affiliation: Institute of Theoretical and Experimental Biophysics, Russian Academy of Science, Institutskaya 3, Pushchino, Moscow Region 142290, Russia. Electronic address: onletaet@gmail.com.
authors.forename: Edward V
authors.initials: EV
authors.lastname: Evdokimovskii
authors.affiliation: Institute of Theoretical and Experimental Biophysics, Russian Academy of Science, Institutskaya 3, Pushchino, Moscow Region 142290, Russia. Electronic address: goicr@rambler.ru.
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Maltsev
authors.affiliation: Institute of Theoretical and Experimental Biophysics, Russian Academy of Science, Institutskaya 3, Pushchino, Moscow Region 142290, Russia; Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555, USA. Electronic address: mnnenov@utmb.edu.
authors.forename: Miroslav N
authors.initials: MN
authors.lastname: Nenov
authors.affiliation: Institute of Cell Biophysics, Russian Academy of Sciences, Institutskaya 3, Pushchino, Moscow Region 142290, Russia. Electronic address: olga.nakipova@gmail.com.
authors.forename: Olga V
authors.initials: OV
authors.lastname: Nakipova
authors.affiliation: Institute of Cell Biophysics, Russian Academy of Sciences, Institutskaya 3, Pushchino, Moscow Region 142290, Russia. Electronic address: averinas82@gmail.com.
authors.forename: Alexey S
authors.initials: AS
authors.lastname: Averin
authors.affiliation: Institute of Theoretical and Experimental Biophysics, Russian Academy of Science, Institutskaya 3, Pushchino, Moscow Region 142290, Russia. Electronic address: poleg237@rambler.ru.
authors.forename: Oleg Yu
authors.initials: OY
authors.lastname: Pimenov
authors.affiliation: Institute of Cell Biophysics, Russian Academy of Sciences, Institutskaya 3, Pushchino, Moscow Region 142290, Russia. Electronic address: T.I.Y@mail.ru.
authors.forename: Ilia Y
authors.initials: IY
authors.lastname: Teplov
authors.affiliation: Institute of Cell Biophysics, Russian Academy of Sciences, Institutskaya 3, Pushchino, Moscow Region 142290, Russia. Electronic address: g_56@rambler.ru.
authors.forename: Alexey V
authors.initials: AV
authors.lastname: Berezhnov
authors.affiliation: Division of Cardiovascular Diseases, Department of Molecular Pharmacology and Experimental Therapeutics, Stabile 5, Mayo Clinic, 200 1st Street SW, Rochester, MN 55905, USA. Electronic address: reyesramirez.santiago@mayo.edu.
authors.forename: Santiago
authors.initials: S
authors.lastname: Reyes
authors.affiliation: Division of Cardiovascular Diseases, Department of Molecular Pharmacology and Experimental Therapeutics, Stabile 5, Mayo Clinic, 200 1st Street SW, Rochester, MN 55905, USA. Electronic address: alekseev.alexey@mayo.edu.
authors.forename: Alexey E
authors.initials: AE
authors.lastname: Alekseev
mesh_terms: D058647:Adrenergic alpha-2 Receptor Agonists / Q000494:pharmacology; D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects; D006332:Cardiomegaly / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006152:Cyclic GMP / Q000378:metabolism; D004195:Disease Models, Animal; D008297:Male; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D054648:Protein Phosphatase 2 / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism*; D017476:Receptors, Neuropeptide Y / Q000819:agonists / Q000378:metabolism; D012508:Sarcolemma / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D058647:Adrenergic alpha-2 Receptor Agonists; D018341:Receptors, Adrenergic, alpha-2; D017476:Receptors, Neuropeptide Y; D009569:Nitric Oxide; C109491:neuropeptide Y4 receptor; D054648:Protein Phosphatase 2; D006152:Cyclic GMP
keywords: Adrenergic stress; Cardiac hypertrophy; Heart failure; Intracellular Ca(2+); Norepinephrine; Protein phosphatase; Spontaneously hypertensive rats (SHR)