THE MODULATION OF CALCIUM CURRENTS BY THE ACTIVATION OF MCLURS - FUNCTIONAL IMPLICATIONS

Glutamatergic transmission in the central nervous system (CNS) is medi ated by ionotropic, ligand-gated receptors (iGluRs), and metabotropic receptors (mGluRs). mGluRs are coupled to GTP-binding regulatory prote ins (G-proteins) and modulate different second messenger pathways. Mul tiple effects have been described following their activation; among ot hers, regulation of fast synaptic transmission, changes in synaptic pl asticity, and modification of the threshold for seizure generation. So me of the major roles played by the activation of mGluRs might depend on the modulation of high-voltage-activated (HVA) calcium (Ca2+) curre nts. Some HVA Ca2+ channels (N-, P-, and Q-type channels) are signalin g components at most presynaptic active zones. Their mGluR-mediated in hibition reduces synaptic transmission. The interference, by agonists at mGluRs, on L-type channels might affect the repetitive neuronal fir ing behavior and the integration of complex events at the somatic leve l. In addition, the mGluR-mediated effects on voltage-gated Ca2+ signa ls have been suggested to strongly influence neurotoxicity. Rather dif ferent coupling mechanisms underlie the relation between mGluRs and Ca 2+ currents: Together with a fast, membrane-delimited mechanism of act ion, much slower responses, involving intracellular second messengers, have also been postulated. In the recent past, the relative paucity o f selective agonists and antagonists for the different subclasses of m GluRs had hampered the clear definition of the roles of mGluRs in brai n function. However, the recent availability of new pharmacological to ols is promising to provide a better understanding of the neuronal fun ctions related to different mGluR subtypes. The analysis of the mGluR- mediated modulation of Ca2+ conductances will probably offer new insig hts into the characterization of synaptic transmission and the develop ment of neuroprotective agents.