Cholinergic and Glutaminergic Excitation of Neuronal Cells

Abstract

Excessive cholinergic or glutaminergic brain stimulation may result in seizures, excitotoxicity and neuronal damage. Cholinergic neuronal excitation is mediated via muscarinic receptors which couple with GTP-binding proteins (G–proteins), activate phospholipase C, and produce the inositol lipid second messengers, inositol-1,4,5,-trisphosphate (InsP3) and diacyl-glycerol (DG). InsP3 facilitates intracellular Ca2+ metabolism and DG activates protein kinase C (PKC). Glutaminergic neuronal stimulation is mediated through ionotropic N-methyl-D-aspartate (NMDA) receptors, which increase Ca2+ influx, and kainate α-amino-3-hydroxy-5-methyl-4-isoxalolproprionic acid receptors, which mainly regulate Na+ fluxes. Glutaminergic metabotropic receptors are also coupled to a G-protein, and their stimulation activates neurons through increased production of InsP3 and DG. A salient feature in glutamate-induced excitotoxicity is the induction of an oxidative burst, subsequent oxidative stress, and damage to the neurons. The glutamate-induced oxidative 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 neuronal cells and this is associated with elevations of free intracellular calcium. The ability of an NMDA receptor antagonist, AP-5, to block carbachol-induced elevations of free intracellular calcium, suggests that activation of muscarinic receptors is associated with a simultaneous glutamate receptor activation. Thus, cross-talk between cholinergic muscarinic and glutaminergic receptors may be an important contributing factor in cholinergic and glutaminergic excitotoxicity.