Activation of cardiac ryanodine receptors by the calcium channel agonist FPL-64176

J. Andrew Wasserstrom, Leslie A. Wasserstrom, Andrew J. Lokuta, James E. Kelly, Sireen T. Reddy, Andrew J. Frank

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

We investigated the possibility that the Ca2+ channel agonist FPL-64176 (FPL) might also activate the cardiac sarcoplasmic reticulum (SR) Ca2+ release channel ryanodine receptor (RyR). The effects of FPL were tested on single channel activity of purified and crude vesicular RyR (RyR2) isolated from human and dog hearts using the planar lipid bilayer technique. FPL (100-200 μM) increased single channel open probability (Po) when added to the cytoplasmic side of the channel (Po = 0.070 ± 0.021 in control RyR2; 0.378 ± 0.086 in 150 ≇M FPL, n = 9, P < 0.01) by prolonging open times and decreasing closed times without changing current magnitude. FPL had no effect on Po when added to the trans (luminal) side of the bilayer (Po = 0.079 ± 0.036 in control and 0.103 ± 0.066 in FPL, n = 4, no significant difference). The bell-shaped [Ca2+] dependence of [3H]ryanodine binding and of Po was altered by FPL, suggesting that the mechanism by which FPL increases channel activity is by an increase in Ca2+-induced activation at low [Ca2+] (without a change in threshold) and suppression of Ca2+-induced inactivation at high [Ca2+]. However, the fact that inactivation was restored at elevated [Ca2+] suggests a competitive interaction between Ca2+ and FPL on inactivation. FPL had no effect on RyR skeletal channels (RyR1), where Po was 0.039 ± 0.005 in control versus 0.030 ± 0.006 in 150 μM FPL (no significant difference). These results suggest that, in addition to its ability to activate the L-type Ca2+ channels, FPL activates cardiac RyR2 primarily by reducing the Ca2+ sensitivity of inactivation.

Original languageEnglish (US)
Pages (from-to)H331-H338
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume283
Issue number1 52-1
DOIs
StatePublished - 2002

Keywords

  • Calcium release channel
  • Dog
  • Heart
  • Human
  • Sarcoplasmic reticulum

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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