Gradation of Ca(2+)‐induced Ca2+ release by voltage‐clamp pulse duration in potentiated guinea‐pig ventricular myocytes.

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Abstract
1. This study tests the hypothesis that whole‐cell cardiac SR Ca2+ release is graded by recruitment of independent ‘release units’. Structurally, an individual release unit may comprise ca four sarcolemmal L‐type Ca2+ channels, adjacent ryanodine‐sensitive sarcoplasmic reticulum (SR) Ca2+ release channels and the junctional gap between them. After depolarization, the first opening of a single L‐type Ca2+ channel of the unit provides sufficient Ca2+ influx to increase local [Ca2+] beyond the threshold activating Ca(2+)‐induced Ca2+ release (CICR), which amplifies local [Ca2+] until all release channels of the unit are active. This all‐or‐none activation does not spread to other release units. Gradation of whole‐cell Ca2+ release is predicted to correlate with the cumulative probability density distribution of first latency of L‐type Ca2+ channels or the activation time course of the calcium current, ICa. 2. Guinea‐pig ventricular myocytes were potentiated by paired voltage‐clamp pulses (1 Hz, 2 mM [Ca2+]o, 40 microM K5‐indo‐1, 36 degrees C). When the cellular Ca2+ load was at a steady high level, cytosolic calcium concentration ([Ca2+]c) transients were measured in response to test pulses of varied pulse duration (PD, 1‐180 ms) and amplitude (‐20, 0, 20 and 50 mV). The maximal rate of rise (RRmax) of the [Ca2+]c transient was used as an indicator for SR Ca2+ release. 3. Fast [Ca2+]c transients due to 4 ms pulses to 0 or 50 mV were blocked by 1 mM cadmium suggesting that these Ca2+ release signals are triggered by Ca2+ influx through L‐type Ca2+ channels and not by Ca2+ influx through Na(+)‐Ca2+ exchange. 4. RRmax increased with longer PD along the sigmoidal curve [1‐exp(‐PD/tau)]kappa(exponent k: 2 < k < 3). The time constant, tau, resembled the activation time constant of whole‐cell ICa (Cs(+)‐dialysed cells). A PD longer than a limiting duration did not modify RRmax. That is, inactivation of ICa was not reflected in the duration dependence. 5. Single L‐type Ca2+ channels (cell‐attached patches, 36 degrees C, ‐20 mV, 3.6 mM CaCl2 and 1 microM Bay K 8644 in patch pipette) opened with a waiting time the cumulative probability distribution of which resembled the duration dependence of RRmax, suggesting that the first opening of L‐type Ca2+ channels determines whether the corresponding release unit contributes to the [Ca2+]c transient activated during a short voltage‐clamp pulse. 6. The time constant, tau, of the duration dependence was shorter at positive than at negative potentials.(ABSTRACT TRUNCATED AT 400 WORDS)

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