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

J Physiol. 2001 Oct 15;536(Pt 2):387-96. doi: 10.1111/j.1469-7793.2001.0387c.xd.


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 (I(Ca)). 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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Caffeine / pharmacology
  • Calcium / metabolism
  • Calcium Channels, L-Type / metabolism*
  • Carbonyl Cyanide m-Chlorophenyl Hydrazone / pharmacology
  • Cytosol / metabolism
  • Fluorescent Dyes
  • Fura-2
  • Indicators and Reagents / pharmacology
  • Male
  • Membrane Potentials / drug effects
  • Membrane Potentials / physiology
  • Mitochondria / metabolism*
  • Muscle Fibers, Skeletal / metabolism
  • Myocardial Contraction / physiology
  • Myocardium / cytology
  • Myocardium / metabolism*
  • Patch-Clamp Techniques
  • Phosphodiesterase Inhibitors / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Ruthenium Compounds / pharmacology
  • Ruthenium Red / pharmacology
  • Uncoupling Agents / pharmacology


  • Calcium Channels, L-Type
  • Fluorescent Dyes
  • Indicators and Reagents
  • Phosphodiesterase Inhibitors
  • Ru 360
  • Ruthenium Compounds
  • Uncoupling Agents
  • Ruthenium Red
  • Caffeine
  • Carbonyl Cyanide m-Chlorophenyl Hydrazone
  • Calcium
  • Fura-2