GLUTAMATE RECEPTORS AND GENE INDUCTION - SIGNALING FROM RECEPTOR TO NUCLEUS

Activation of glutamate receptors has been linked to a diversity of la sting physiologic and pathologic changes in the mammalian nervous syst em. The cellular and molecular mechanisms underlying permanent modific ations of nervous system structure and function following brief episod es of neuronal activity are unknown. Immediate early genes (IEGs) have been implicated in the conversion of short-term stimuli to long-term changes in cellular phenotype by regulation of gene expression. Many o f the long-term consequences of glutamate receptor activation correlat e with increases in specific IEGs; the intracellular signalling pathwa ys coupling activation of receptors at the cell surface with induction of IEGs in the nucleus are incompletely understood. Analysis of mecha nisms of how extracellular factors control gene expression implicate a ctivation of second messenger systems and protein kinases. Activation of glutamate receptors results in an initial increase in intracellular calcium; the route of calcium influx may differ depending on the spec ific receptor subtype activated. Intracellular calcium is often the fi rst messenger in response to an extracellular stimulus and can be the trigger for activating numerous other signalling pathways. Results obt ained over the past several years support a hypothesis where selective activation of distinct intracellular signalling pathways and IEG resp onses, following activation of different glutamate receptor subtypes, involve spatial restriction of key enzymes to sites of local calcium i ncreases. The specificity in long-term neuronal responses following br ief synaptic activation may depend on the specific intracellular signa lling mechanisms triggered and the unique array of IEGs transcribed. ( C) 1997 Elsevier Science Inc.