Ampa and Kainate Receptors in Cns Injury*

Glutamate receptors are the most common excitatory neurotransmitter receptors in the central nervous system (CNS). Excessive stimulation of glutamate receptors, including receptors of the AMPA and kainate families, is believed to contribute to the neurodegeneration encountered in stroke, CNS trauma, and several degenerative neurologic disorders. Animal models also suggest that AMPA and kainate receptors participate in the killing of oligodendrocytes, which raises the possibility that these receptors may be important in the pathogenesis of multiple sclerosis. Animal models in which kainate-induced seizures produce delayed neurodegeneration in hippocampal CA1 and CA3 regions suggest that one subunit of AMPA receptors, known as GluR2, is particularly important in the development of delayed neurodegeneration. Recent discovery of a silencer mechanism that regulates GluR2 expression raises the possibility of novel therapeutic interventions that specifically target mechanisms of neurodegeneration common to a number of disorders of the CNS. (Adv Stud Med. 2004;4(4B):S331-S334) G lutamate receptors are the principal excitatory neurotransmitter receptors in the mammalian brain. Glutamatemediated influx of Ca2+ into neurons of the central nervous system (CNS) is particularly important during CNS development and in learning and memory. Glutamate receptors are also central to the pathophysiologic processes that produce injury to neurons and glial cells in CNS ischemia, trauma, epilepsy, and possibly in neurodegenerative conditions such as Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease. Two broad classes of glutamate receptors have been described. Inotropic receptors, which mediate most of the excitatory neurotransmission in the CNS, are ligandgated channels that regulate ion flow through the neuron cell membrane in response to changing concentrations of extracellular glutamate. Metabotropic glutamate receptors indirectly influence neuron function by activating intracellular “second messenger” systems. The ionotropic receptors are further subdivided, based on their sensitivity to specific agonists, into 3 classes: N-methyl-D-aspartate (NMDA) receptors, AMPA receptors, and kainate receptors. Inotropic glutamate receptors are composed of several distinct receptor subunits, and the particular combination of subunit types varies from receptor to receptor. AMPA receptors are composed of 4 subunits, which are labeled GluR1 through GluR4. Kainate receptors are composed of a different set of subunits (GluR5 through GluR7 and KA1 and KA2). Pharmacologic studies suggest that each of these receptor subunits may be susceptible to pharmacologic manipulation by subunit-specific modulating agents. For example, the activity of most of the kainate receptor subunit types is inhibited by protons, but receptors containing KA1 subunits increase their responsiveness PROCEEDINGS