Reciprocal regulation of fatty acid release in the brain by GABA and glutamate.
Several model systems have been used to test the hypothesis that the release of FFA in the brain is regulated by depolarization of neurons. This FFA release is likely the result of the activation of phospholipase A2. The increased neuronal activity that occurs due to synchronous depolarization during seizures causes activation of phospholipase A2. Decreasing neuronal activity by administering the anxiolytic, diazepam, appears to decrease the activity of phospholipase A2. The GABA antagonist, bicuculline, which causes depolarization by negating the hyperpolarizing tone imposed on neurons by GABA, causes FFA release in synaptosomes and in neurons in tissue culture. Likewise, the glutamate agonist, kainic acid, which depolarizes neurons by opening sodium channels, increases the activity of phospholipase A2. PC-specific phospholipase C, another enzyme important in the generation of the second messenger, DG, is also activated by depolarization. Several important questions remain to be answered. The site of FFA release, in terms of the pre-vs. postsynaptic membrane, is not clear, although the experiments with synaptosomes support the hypothesis that activation of phospholipase A2 may be an important regulator of presynaptic events. This idea has also been suggested by studies on the phenomenon of long-term potentiation, where free 20:4 or its metabolites may be involved in presynaptic facilitation of neurotransmitter release (Freeman et al., 1990; Massicotte et al., 1990; Williams et al., 1989; also see Dorman, this volume). The activation of the PI cycle and subsequent stimulation of protein kinase C may be a postsynaptic event important in the integration of inputs at the dendrite and soma or a presynaptic event involved in the modulation of neurotransmitter release (Taniyama et al., 1990; El-Fakahany et al., 1990; also see Nishizuka, this volume). Therefore the stimulation of a PC-specific phospholipase C, which is capable of generating large amounts of DG over a prolonged period of time (Exton, 1990; Martinson et al., 1990; Diaz-Laviada et al., 1990), could occur at either site. Another important question is the role of FFA and DG in affecting cell-cell signaling events, particularly with regard to ion fluxes. Modulation of an acetylcholine-linked K+ channel in the heart by FFA and their oxygenation products has been reported (Kim and Clapham, 1989). The cardiac muscarinic receptor is linked to a hyperpolarizing K+ channel via a G protein.(ABSTRACT TRUNCATED AT 400 WORDS)
Department of Pharmacology and Toxicology, West Virginia University, Morgantown.
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D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D003975:Diazepam / Q000494:pharmacology; D004075:Diglycerides / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism*; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D005971:Glutamates / Q000378:metabolism; D018698:Glutamic Acid; D007608:Kainic Acid / Q000494:pharmacology; D051381:Rats; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D004075:Diglycerides; D005227:Fatty Acids; D005230:Fatty Acids, Nonesterified; D005971:Glutamates; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D003975:Diazepam; D007608:Kainic Acid