Modulation of the Ca2+-induced Ca2+ release cascade by β-adrenergic stimulation in rat ventricular myocytes
Article first published online: 5 AUG 2004
The Journal of Physiology
Volume 533, Issue 3, pages 837–848, June 2001
How to Cite
Viatchenko-Karpinski, S. and Györke, S. (2001), Modulation of the Ca2+-induced Ca2+ release cascade by β-adrenergic stimulation in rat ventricular myocytes. The Journal of Physiology, 533: 837–848. doi: 10.1111/j.1469-7793.2001.t01-1-00837.x
- Issue published online: 5 AUG 2004
- Article first published online: 5 AUG 2004
- (Received 21 September 2000; accepted after revision 13 February 2001)
- 1To define the sub-cellular mechanisms of modulation of cardiac excitation-contraction (E-C) coupling by the β-adrenergic pathway, we carried out confocal Ca2+ imaging in conjunction with recordings of inward Ca2+ current in fluo-3-loaded patch-clamped rat ventricular myocytes.
- 2Isoproterenol (isoprenaline; ISO) increased the amplitude of the inward Ca2+ current and the globally measured intracellular Ca2+ transients. The gain of calcium-induced calcium release (CICR) was increased at all membrane potentials but especially at positive membrane potentials (> +30 mV). ISO dramatically broadened the bell-shaped voltage dependence of intracellular Ca2+ transients by shifting the descending portion of the curve to very high membrane potentials.
- 3The number of local release events (solitary sparks and conglomerates of overlapping sparks) induced by depolarizing steps to +30 mV was increased significantly by ISO. This potentiation of events was due to increased trigger calcium current (ICa) as well the enhanced ability of ICa to induce release. The amplitude and duration of solitary sparks were increased in the presence of ISO. In addition, ISO dramatically increased the proportion and the size (‘mass’) of clustered events.
- 4Exclusion of Na+ from the intra- and extracellular solutions prevented ISO from enhancing the ability of ICa to trigger sparks.
- 5We conclude that β-adrenergic stimulation enhances the gain of the CICR cascade by increasing the fidelity of dihydropyridine receptor (DHPR)-ryanodine receptor (RyR) coupling and by promoting cross-activation of RyRs in neighbouring release sites. Reverse Na+-Ca2+ exchange (NCX) appears to play a role in the β-adrenergic enhancement of CICR by effectively contributing to the Ca2+ trigger.