Palmitoyl-CoA potentiates the Ca²⁺ release elicited by cyclic ADP-ribose

Cyclic ADP-ribose (cADPR) is a potent mediator of Ca²⁺ mobilization from intracellular stores in sea urchin eggs that ultimately activates the ryanodine channel. We now report that certain long-chain acyl-CoA derivative metabolites (14-18 carbons in length), such as palmitoyl-CoA, greatly potentiate the effect of cADPR on Ca²⁺ release. Furthermore, in higher concentrations, palmitoyl-CoA and other closely related long-chain acyl-CoA derivatives trigger Ca²⁺ release apparently through the ryanodine channel in sea urchin egg homogenates. Palmitoyl-CoA-induced Ca²⁺ release was suppressed by ruthenium red, spermine, and the calmodulin antagonist N-(6-aminohesyl)-1-naphthalenesulfonamide, which all prevent activation of the ryanodine channel, but not by heparin or thionicotinamide-NADP. In addition, cADPR was able to desensitize the sea urchin egg homogenates to the subsequent Ca²⁺ release induced by palmitoyl-CoA and vice versa. In contrast, neither inositol 1,4,5-trisphosphate (IP₃) nor the newly identified Ca²⁺ release agonist nicotinate adenine dinucleotide phosphate was able to desensitize the homogenate to palmitoyl-CoA, indicating that palmitoyl-CoA probably acts selectively by activating the ryanodine channel, but, unlike cADPR, palmitoyl-CoA might act directly on this channel. Finally, we found that palmitoyl-CoA was able to counteract the inhibitory effect of Mg²⁺ and spermine, which, in physiological concentrations, suppress specifically the cADPR-induced Ca²⁺ release. We propose that palmitoyl-CoA, present in micromolar concentrations, may trigger Ca²⁺ release through the ryanodine channel and, in lower concentrations, may increase the sensitivity of the Ca²⁺ release system to cADPR. Thus palmitoyl-CoA may serve as a regulatory link between the intermediary metabolism and the cADPR-induced Ca²⁺ release signaling pathway.