Ca2+ release-induced inactivation of Ca2+ current in rat ventricular myocytes: Evidence for local Ca2+ signalling

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1. Inactivation of Ca2+ current (I(Ca)) induced by Ca2+ release from sarcoplasmic reticulum (SR) was studied in single rat ventricular myocytes using whole-cell patch-clamp and indo-1 fluorescence measurement techniques. 2. Depolarizing pulses to 0 mV elicited large Ca2+ transients and I(Ca) with biexponential inactivation kinetics. Varying SR Ca2+ loading by a 20 s pulse of caffeine showed that the fast component of I(Ca) inactivation was dependent on the magnitude of Ca2+ release. 3. Inactivation of I(Ca) induced by Ca2+ release was quantified, independently of voltage and Ca2+ entry, using a function termed fractional inhibition of I(Ca)(FI(Ca)). The voltage relation of FI(Ca) had a negative slope, resembling that of single-channel Ca2+ current (i(Ca)) rather than the bell-shaped current-voltage (I-V) relation of macroscopic I(Ca) and Ca2+ transients. 4. Intracellular dialysis of myocytes with 10 mM EGTA (150 nM free [Ca2+]) had no effect on I(Ca) inactivation induced by Ca2+ release, despite abolition of Ca2+ transients and cell contraction. Dialysis with 3 or 10 mM BAPTA (180 nM free [Ca2+]) attenuated FI(Ca) in a concentration-dependent manner, with greater inhibition at positive than at negative potentials, consistent with more effective buffering of Ca2+ microdomains of smaller i(Ca). 5. Spatial profiles of [Ca2+] near an opened Ca2+ channel were simulated. [Ca2+] reached submillimolar levels at the mouth of the channel, and dropped steeply as radial distance increased. At any given distance from the channel, [Ca2+] was higher at negative than at positive potentials. The radii of Ca2+ microdomains were significantly reduced by 3 or 10 mM BAPTA, but not by 10 mM EGTA. 6. In conclusion, the distinctive voltage dependence and susceptibility of Ca2+ release-induced I(Ca) inactivation to fast and slow Ca2+ buffers suggests that the process is mediated through local changes of [Ca2+] in the vicinity of closely associated Ca2+ channels and ryanodine receptors.

Original languageEnglish (US)
Pages (from-to)285-295
Number of pages11
JournalJournal of Physiology
Issue number2
StatePublished - Apr 15 1997

ASJC Scopus subject areas

  • Physiology


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