Genetic regulation of glutamate receptor ion channels

Transcriptional and translational regulation of glutamate receptor expressi on determines one of the key phenotypic features of neurons in the brain-th e properties of their excitatory synaptic receptors. Up- and down-regulatio n of various glutamate receptor subunits occur throughout development, foll owing ischemia, seizures, repetitive activation of afferents, or chronic ad ministration of a variety of drugs. The promoters of the genes that encode the NR1, NR2B, NR2C, GluR1, GluR2, and KA2 subunits share several character istics that include multiple transcriptional start sites within a CpG islan d, lack of TATA and CAAT boxes, and neuronal-selective expression. In most cases, the promoter regions include overlapping Sp1 and GSG motifs near the major initiation sites, and a silencer element, to guide expression in neu rons. Manipulating the levels of glutamate receptors in vivo by generating transgenic and knockout mice has enhanced understanding of the role of spec ific glutamate receptor subunits in long-term potentiation and depression, learning, seizures, neural pattern formation, and survival. Neuron-specific glutamate receptor promoter fragments may be employed in the design of nov el gene-targeting constructs to deliver future experimental transgene and t herapeutic agents to selected neurons in the brain.