Diacylglycerols release LH: structure-activity relations reveal a role for protein kinase C

A series of diacylglycerols were synthesized with varying lengths and substituents in order to establish the structure-activity relationship between each with activation of protein kinase C and stimulation of a biological response system (pituitary luteinizing hormone release). This approach enables distinction between actions mediated by direct activation of protein kinase C and those due to other, presumably nonspecific, actions. The ability of diacylglycerols to function as regulators of a biological response system (pituitary luteinizing hormone release) and of protein kinase C was investigated with a series of sn-1,2 diacylglycerols containing fatty acids 4-10 carbons in length and with analogs in which the 3' hydroxyl was replaced with a chloro, hydrogen, or sulfhydryl moiety. Several diacylglycerols stimulated LH release in a saturable, time and dose dependent manner that was independent of extra-cellular calcium. Dioctanoylglycerol (diC8) was the most effective of the diacylglycerols tested; 3' analogs lacking the hydroxyl were inactive. The diacylglycerols activated protein kinase C in vitro whereas the 3' analogs did not. These data implicate protein kinase C in the mechanism of LH release, demonstrate that unsaturated fatty acyl moieties within the diacylglycerol are not required for protein kinase C activation, and establish diacylglycerol-protein kinase C structure-function relationships that should prove useful for investigations in other systems.