Membrane-Delimited Stimulation of Heart Cell Calcium Current by ß-Adrenergic Signal-Transducing Gs Protein
A several-fold increase in calcium current (Ica) is a signal feature of the maximal beta-adrenergic response of the heart. It is generally ascribed to enhanced adenosine 3’,5’-cyclic monophosphate (cAMP)dependent phosphorylation of calcium (Ca) channels following beta-receptor activation of the guanosine nucleotide-binding (G) protein Gs, and Gs-activation of the adenylyl cyclase cascade. We blocked phosphorylation pathways in guinea pig ventricular cardiomyocytes to unmask other possible Ica-stimulatory modes. In blocked cells, Ica increased by approximately 50% during (i) beta-receptor activation of Gs, (ii) intracellular activation of Gs, and (iii) intracellular application of preactivated Gs. We conclude that fast, membrane-delimited Gs modulation participates in the physiological regulation of cardiac Ica. Additionally, membrane-delimited action by activated Gs seems to hinder Ca channel inhibition by D600 and may prime Ca channels for up-regulation by cAMP-dependent phosphorylation.
Key wordsCardiomyocytes-Calcium current regulation-Activated Gs protein
Unable to display preview. Download preview PDF.
- Brown AM, Kunze DL, Yatani A (1984) Dual effects of dihydropyridines on whole cell and unitary calcium currents in single ventricular cells of guinea-pig. J Physiol (Lond) 379: 495–514Google Scholar
- Codina J, Hildebrandt JD, Sekura RD, Birnbaumer M, Bryan J, Manclark CR, Iyengar R, Birnbaumer L (1984a) Ns and NI, the stimulatory and inhibitory regulatory component of adenylyl cyclases: purification of the human erythrocyte proteins without the use of activating regulatory ligands. J, Biol Chem 259: 5871–5886.Google Scholar
- Hartzell HC, Fischmeister R (1987) Effect of forskolin and acetylcholine on calcium current in single isolated cardiac myocytes. Molec Pharmacol 32: 639–645Google Scholar
- Isenberg G, Cerbai E, Klöckner U (1987) Ionic channels and adenosine in isolated heart cells. In: Gerlach E, Becker BF (eds) Topics and perspectives in adenosine research. Springer Berlin Heidelberg New York, pp 323–335Google Scholar
- Kaczmarek LK (1987) The role of protein kinase C in the regulation of ion channels and neurotransmitter release Trends Neurosci 10: 30–34Google Scholar
- Kokubun S, Prod’hom B, Becker C, Porzig H, Reuter H (1986) Studies on Ca channels in intact cardiac cells: voltage-dependent effects and cooperative interactions of dihydropyridine enantiomers. Molec Pharmacol 30: 571–584Google Scholar
- McDonald TF, MacLeod DP (1973) DNP-induced dissipation of ATP in anoxic ventricular muscle. J Physiol (Lond) 229: 583–599Google Scholar
- McDonald TF, Pelzer D, Trautwein W (1989) Dual action (stimulation, inhibition) of D600 on contractility and calcium channels in guinea-pig and cat heart cells. J Physiol (Lond) 414: 569–586Google Scholar
- Simmons MA, Hartzell HC (1988) Role of phosphodiesterase in regulation of calcium current in isolated cardiac myocytes. Molec Pharmacol 33: 664–671Google Scholar
- Shuba, YM, Hesslinger B, Trautwein W, McDonald TF, Pelzer D (1990b) Whole-cell calcium current in guinea-pig ventricular myocytes dialysed with guanine nucleotides. J Physiol (Lond) 424: 205–228Google Scholar
- Trautwein W, Cavalié A, Allen TJA, Shuba, YM, Pelzer S, Pelzer D (1990) Direct and indirect regulation of cardiac L-type calcium channels by B-adrenoceptor agonists. In: Nishizuka Y et al. (eds) The biology and medicine of signal transduction. Raven Press New York, pp 45–50Google Scholar
- Yatani A, Imoto Y, Codina J, Hamilton SL, Brown AM, Birnbaumer L (1988) The stimulatory G protein of adenylyl cyclase, Gs, also stimulated dihydropyridine-sensitive Cat channels. Evidence for direct regulation independent of phosphorylation by camp-dependent protein kinase or stimulation by a dihydropyridine agonist. J Biol Chem 263: 9887–9895PubMedGoogle Scholar