ACTIVATION OF THE CA-2+ RELEASE CHANNEL OF SKELETAL-MUSCLE SARCOPLASMIC-RETICULUM BY PALMITOYL CARNITINE

Studies of [H-3]ryanodine binding, Ca-45(2+) efflux, and single channel recordings in planar bilayers indicated that the fatty acid metabolite palmitoyl carnitine produced a direct stimulation of the Ca2+ release channel (ryanodine receptor) of rabbit and pig skeletal muscle junctional sarcoplasmic reticulum. At a concentration of 50 muM, palmitoyl carnitine (a) stimulated [H-3]ryanodine binding 1.6-fold in a competitive manner at all pCa in the range 6 to 3; (b) released approximately 65% (30 nmol) of passively loaded Ca-45(2+)/Mg protein; and (c) increased 7-fold the open probability of Ca2+ release channels incorporated into planar bilayers. Neither carnitine nor palmitic acid could reproduce the effect of palmitoyl carnitine on [H-3]ryanodine binding, Ca-45(2+) release, or channel open probability, Ca-45(2+) release was induced by several long-chain acyl carnitines (C-14, C-16, C18) and acyl coenzyme A derivatives (C-12, C-14, C-16), but not by the short-chain derivative C, or by free saturated fatty acids of chain length C-8 to C18, at room temperature or 36-degrees-C. This newly identified interaction of esterified fatty acids and ryanodine receptors may represent a pathway by which metabolism of skeletal muscle could influence intracellular Ca2+ and may be responsible for the pathophysiology of disorders of beta-oxidation such as carnitine palmitoyl transferase II deficiency.