Ethanol is thought to exert many of its behavioral and biochemical effects through a physical interaction with biomembranes. A primary function of plasma membranes in many cell types is the transduction of biochemical signals from outside the cell into intracellular messengers. This function underlies the phenomenon of synaptic transmission between neurons and hormonal activation of peripheral cells such as in the liver. The brain and liver are two organs which are clearly affected by the ingestion of ethanol acutely, and both organs are known to be damaged after chronic ethanol ingestion. Although membranes seem to be a primary locus for ethanol action, information is lacking about ethanol's effects on membrane signal transduction mechanisms. In particular, receptor-stimulated phosphoinositide (PI) hydrolysis has been implicated to be an important biochemical signal transduction system in both brain and liver. Neurotransmitters or hormones bind to specific cell surface receptors which results in the hydrolysis of phosphoinositides by a specific phospholipase C. Thus, inositol trisphospate and diacylglycerol are released and may act as second messengers inside the cell to release intracellular calcium and activate protein kinase C, respectively. This proposal will investigate the possibility that guanine nucleotide binding proteins are involved in the coupling of the receptor to the response in brain, and look at the proposed calcium releasing properties of inositol trisphosphate in brain membranes. Further experiments will then determine the effects of ethanol on the PI hydrolysis system in brain and liver. Preliminary experiments have established that ethanol in vitro and chronically in vivo can alter receptor-stimulated PI responses in brain and liver. Therefore, experiments are proposed to further characterize the mechanism of ethanol's effects on PI responses and test whether ethanol-induced alterations in receptor- stimulated PI responses lead to further changes in cell function (calcium mobilization in brain and liver, phosphorylase activation in liver). These experiments may lead to further knowledge of receptor functions in general, and may provide additional information concerning the pharmacology and/or toxicology of alcohol.
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