Modulation of the Ca2+-induced Ca2+ release cascade by {beta}-adrenergic stimulation in rat ventricular myocytes

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Modulation of the Ca²⁺-induced Ca²⁺ release cascade by $beta$ -adrenergic stimulation in rat ventricular myocytes

Serge Viatchenko-Karpinski and Sandor Györke

Department of Physiology, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA

To define the sub-cellular mechanisms of modulation of cardiac excitation-contraction (E-C) coupling by the $beta$ -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.
Isoproterenol (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.
The 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 (I_Ca) as well the enhanced ability of I_Ca 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.
Exclusion of Na⁺ from the intra- and extracellular solutions prevented ISO from enhancing the ability of I_Ca to trigger sparks.
We conclude that $beta$ -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 $beta$ -adrenergic enhancement of CICR by effectively contributing to the Ca²⁺ trigger.

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