CHOLINERGIC AND GLUTAMINERGIC EXCITATION OF NEURONAL CELLS

Excessive cholinergic or glutaminergic brain stimulation may result in seizures, excitotoxicity and neuronal damage. Cholinergic neuronal ex citation is mediated via muscarinic receptors which couple with GTP-bi nding proteins (G-proteins), activate phospholipase C, and produce the inositol lipid second messengers, inositol-1,4,5,-trisphosphate (InsP (3)) and diacylglycerol (DG). InsP(3) facilitates intracellular Ca2+ m etabolism and DG activates protein kinase C (PKC). Glutaminergic neuro nal stimulation is mediated through ionotropic N-methyl-D-aspartate (N MDA) receptors, which increase Ca2+ influx, and kainate lpha-amino-3-h ydroxy-5-methyl-4-isoxalolproprionic acid receptors, which mainly regu late Na+ fluxes. Glutaminergic metabotropic receptors are also coupled to a G-protein, and their stimulation activates neurons through incre ased production of InsP(3), and DG. A salient feature in glutamate-ind uced excitotoxicity is the induction of an oxidative burst, subsequent oxidative stress, and damage to the neurons. The glutamate-induced ox idative burst can be amplified by lead, a direct activator of PKC, and the oxidative burst can be blocked by a PKC inhibitor, suggesting an important role for PKC. Carbachol also induces an oxidative burst in n euronal cells and this is associated with elevations of free intracell ular calcium. The ability of an NMDA receptor antagonist, AP-5, to blo ck carbachol-induced elevations of free intracellular calcium, suggest s that activation of muscarinic receptors is associated with a simulta neous glutamate receptor activation. Thus, cross-talk between choliner gic muscarinic and glutaminergic receptors may be an important contrib uting factor in cholinergic and glutaminergic excitotoxicity.