title: Alpha-2 adrenoceptors and imidazoline receptors in cardiomyocytes mediate counterbalancing effect of agmatine on NO synthesis and intracellular calcium handling.
abstract: Evidence suggests that intracellular Ca(2+) levels and contractility of cardiomyocytes can be modulated by targeting receptors other than already identified adrenergic or non-adrenergic sarcolemmal receptors. This study uncovers the presence in myocardial cells of adrenergic α2 (α2-AR) and imidazoline I1 (I1R) receptors. In isolated left ventricular myocytes generating stationary spontaneous Ca(2+) transients in the absence of triggered action potentials, the prototypic agonist of both receptors agmatine can activate corresponding signaling cascades with opposing outcomes on nitric oxide (NO) synthesis and intracellular Ca(2+) handling. Specifically, activation of α2-AR signaling through PI3 kinase and Akt/protein kinase B stimulates NO production and abolishes Ca(2+) transients, while targeting of I1R signaling via phosphatidylcholine-specific phospholipase C (PC-PLC) and protein kinase C (PKC) suppresses NO synthesis and elevates averaged intracellular Ca(2+). We identified that endothelial NO synthase (eNOS) is a major effector for both signaling cascades. According to the established eNOS transitions between active (Akt-dependent) and inactive (PKC-dependent) conformations, we suggest that balance between α2-AR and I1R signaling pathways sets eNOS activity, which by defining operational states of myocellular sarcoplasmic reticulum Ca(2+)-ATPase (SERCA) can adjust Ca(2+) re-uptake and thereby cardiac inotropy. These results indicate that the conventional catalog of cardiomyocyte sarcolemmal receptors should be expanded by the α2-AR and I1R populations, unveiling previously unrecognized targets for endogenous ligands as well as for existing and potential pharmacological agents in cardiovascular medicine.
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. Electronic address: malat_88@mail.ru.
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: poleg237@rambler.ru.
authors.forename: Oleg Y
authors.initials: OY
authors.lastname: Pimenov
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; D000376:Agmatine / Q000494:pharmacology; D000818:Animals; D001572:Benzofurans / Q000494:pharmacology; D020013:Calcium Signaling; D002478:Cells, Cultured; D007093:Imidazoles / Q000494:pharmacology; D054755:Imidazoline Receptors / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism*
chemical_list: D058647:Adrenergic alpha-2 Receptor Agonists; D001572:Benzofurans; D007093:Imidazoles; D054755:Imidazoline Receptors; D018341:Receptors, Adrenergic, alpha-2; D009569:Nitric Oxide; D000376:Agmatine; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; C062597:efaroxan
keywords: Cell signaling; Heart; Ryanodine receptor; SERCA; SR; eNOS