EFFECTS OF ETHANOL ON INOSITOL 1,3,4,5-TETRAKISPHOSPHATE METABOLISM BY RAT-BRAIN HOMOGENATES

The hydrolysis of membrane phosphoinositides is widely recognized as an important signal transduction pathway in brain. One of the products of phosphoinositide hydrolysis, Ins(1,4,5)P3, is thought to participate in signal transduction by mobilizing intracellular calcium and it is now clear that Ins(1,4,5)P3 metabolism is a complicated process that may be highly regulated. In addition to being dephosphorylated by the action of a 5-phosphatase, Ins(1,4,5)P3 can be phosphorylated by a 3-kinase to Ins(1,3,4,5)P4. Although the physiological significance of the higher inositol polyphosphates is not clear, recent evidence suggests that Ins(1,3,4,5)P4 may also have important second messenger function. Since ethanol is known to have potent effects on synaptic transmission, we investigated the in vitro effects of ethanol on [H-3]Ins(1,3,4,5)P4 metabolism by rat whole brain homogenates. Ins(1,3,4,5)P4 was rapidly hydrolyzed to Ins(1,3,4)P3, inositol bisphosphates [Ins(3,4)P2 and Ins(1,3)P2], inositol monophosphates [Ins(1)P/Ins(3)P and Ins(4)P], and to inositol by sequential dephosphorylation. No [H-3]Ins(1,4,5)P3 was detected. Ethanol (500 mM), significantly accelerated the dephosphorylation of Ins(1,4,5)P3, resulting in a more rapid formation of inositol bisphosphates, monophosphates and inositol. However, intoxicating and sedative-hypnotic concentrations of ethanol (30-100 mM) had no effect upon Ins(1,3,4)P3 dephosphorylation, suggesting that pharmacologically relevant concentrations of ethanol do not directly effect the enzymes involved in the dephosphorylation of Ins(1,3,4,5)P4 to free inositol in brain.