Local calcium release activation by DHPR calcium channel openings in rat cardiac myocytes

Abstract

The principal role of calcium current in the triggering of calcium release in cardiac myocytes is well recognized. The mechanism of how calcium current (I Ca ) controls the intensity of calcium release is not clear because of the stochastic nature of voltage-dependent gating of calcium channels (DHPRs) and of calcium-dependent gating of ryanodine receptors (RyRs). To disclose the relation between DHPR openings and the probability of calcium release, local calcium release activation by I Ca was investigated in rat ventricular myocytes using patch-clamp and confocal microscopy. Calcium spikes were activated by temporally synchronized DHPR calcium current triggers, generated by instantaneous 'tail' I Ca and modulated by prepulse duration, by tail potential, and by the DHPR agonist BayK 8644. The DHPR-RyR coupling fidelity was determined from the temporal distribution of calcium spike latencies using a model based on exponentially distributed DHPR open times. The analysis provided a DHPR mean open time of ∼0.5 ms, RyR activation time constant of ∼0.6 ms, and RyR activation kinetics of the 4th order. The coupling fidelity was low due to the inherent prevalence of very short DHPR openings but was increased when DHPR openings were prolonged by BayK 8644. The probability of calcium release activation was high, despite low coupling fidelity, due to the activation of many DHPRs at individual release sites. We conclude that the control of calcium release intensity by physiological stimuli can be achieved by modulating the number and duration of DHPR openings at low coupling fidelity, thus avoiding the danger of inadvertently triggering calcium release events.

Polydatin modulates Ca2+ handling, excitation–contraction coupling and β-adrenergic signaling in rat ventricular myocytes

“…Recent studies have demonstrated that there is a "redundancy" of the trigger I Ca in a diad, that is reducing either the number of individual open channel or single channel current alone increases EC coupling gain [36,37]. I Ca is the ensemble of single channel currents (I Ca ) through That NO decreases the conductance and Po of single LCC current as reported in previous studies [38,39] further supports this notion.…”

Ca 2+ channel nanodomains boost local Ca 2+ amplitude

“…With regard to biochemical signaling cascades, tiny ∼fA Ca 2+ fluxes, generally believed not to partake in local signaling, could produce ∼μM Ca 2+ signals sufficient to signal locally to molecules like CaM or CaMKII (34). Nanodomain boosting may similarly play a role in the contraction of ventricular myocytes, where controversy exists regarding whether activation of ryanodine receptors can be triggered by the opening of a single Ca V channel [high-fidelity scenario supported by early experimental work (35)(36)(37)(38)], or if the simultaneous opening of ∼10 channels is necessary [as suggested by recent models that take account of the small ∼fA flux through a single Ca V channel at the +50 mV ventricular plateau potential (39)(40)(41)]. Our findings may reconcile this low-flux high-fidelity paradox given that a single Ca V channel would, by virtue of nanodomain Ca 2+ boosting, have the potency of ∼10 channels in the absence of this amplification.…”

Excitation–contraction coupling gain in ventricular myocytes: insights from a parsimonious model

“…The third relationship, P trig vs. i Ca , called the 'coupling fidelity' in other studies Altamirano & Bers, 2007;Polakova et al 2008), is not known precisely. However, it stands to reason that P trig will be zero at i Ca = 0 and will reach a saturating level at large values of i Ca .…”