© 1996 American Heart Association, Inc.
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Regulation of Cardiac Ca2+ Release Channel (Ryanodine Receptor) by Ca2+, H+, Mg2+, and Adenine Nucleotides Under Normal and Simulated Ischemic Conditions
the Department of Biochemistry and Biophysics and the Department of Physiology, University of North Carolina, Chapel Hill.
Correspondence to Gerhard Meissner, Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC 27599-7260.
In myocardial ischemia, pHi and [ATP] fall, whereas the free [Ca2+] and [Mg2+] rise. The effects of these changes on cardiac Ca2+ release channel (ryanodine receptor) activity were investigated in [3H]ryanodine binding and single-channel measurements, using isolated membrane and purified channel preparations. In the absence of the two channel ligands Mg2+ and ATP, cardiac Ca2+ release channels were half-maximally activated at pH 7.4 by 
4 µmol/L cytosolic Ca2+ and half-maximally inhibited by 9 mmol/L cytosolic Ca2+. Regulation of channel activity by Ca2+ was modulated by Mg2+ and ATP. Single-channel activities were more sensitive to a change of cytosolic pH than SR lumenal pH. Reduction in lumenal and/or cytosolic pH from 7.3 to 6.5 and 6.0 resulted in decreased single-channel activities without a change in single-channel conductance. [3H]Ryanodine binding measurements also indicated that acidosis impairs cardiac Ca2+ release channel activity. Mg2+ and adenine nucleotide concentrations regulated the extent of inhibition and the Ca2+ dependence of binding. In the presence of 5 mmol/L Mg2+ and 5 mmol/L ß,
-methyleneadenosine 5'-triphosphate (AMPPCP, a nonhydrolyzable ATP analogue), the free [Ca2+] for half-maximal [3H]ryanodine binding was increased from 1.9 µmol/L at pH 7.3 to 36 µmol/L at pH 6.5 and to 89 µmol/L at pH 6.2. These results suggest that ionic and metabolic changes that might be expected to affect sarcoplasmic reticulum Ca2+ release channel activity in ischemic myocardium include an altered Ca2+ sensitivity of the channel, a fall in pH, and a loss of the high-energy adenine nucleotide pool, leading to an increased inhibition by Mg2+.
Key Words: excitation-contraction coupling • ischemia
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