Mitochondria regulate inactivation of L‐type Ca2+ channels in rat heart

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Abstract
1 L‐type Ca2+ channels play an important role in vital cell functions such as muscle contraction and hormone secretion. Both a voltage‐dependent and a Ca2+‐dependent process inactivate these channels. Here we present evidence that inhibition of the mitochondrial Ca2+ import mechanism in rat (Sprague‐Dawley) ventricular myocytes by ruthenium red (RR), by Ru360 or by carbonyl cyanide m‐chlorophenylhydrazone (CCCP) decreases the magnitude of electrically evoked transient elevations of cytosolic Ca2+ concentration ([Ca2+]c). These agents were most effective at stimulus rates greater than 1 Hz. 2 RR and CCCP also caused a significant delay in the recovery from inactivation of L‐type Ca2+ currents (ICa). This suggests that sequestration of cytosolic Ca2+, probably near the mouth of L‐type Ca2+ channels, into mitochondria during cardiac contractile cycles, helps to remove the Ca2+‐dependent inactivation of L‐type Ca2+ channels. 3 We conclude that impairment of mitochondrial Ca2+ transport has no impact on either L‐type Ca2+ currents or SR Ca2+ release at low stimulation frequencies (e.g. 0.1 Hz); however, it causes a depression of cytosolic Ca2+ transients attributable to an impaired recovery of L‐type Ca2+ currents from inactivation at high stimulation frequencies (e.g. 3 Hz). The impairment of mitochondrial Ca2+ uptake and subsequent effects on Ca2+ transients at high frequencies at room temperature could be physiologically relevant since the normal heart rate of rat is around 5 Hz at body temperature. The role of mitochondria in clearing Ca2+ in the micro‐domain near L‐type Ca2+ channels could be impaired during high frequencies of heart beats such as in ventricular tachycardia, explaining, at least in part, the reduction of muscle contractility.