Modification of glutamate receptor channels: Molecular mechanisms and functional consequences

Of the many possible mechanisms for modulating the efficiency of ion channe ls, the phosphorylation of receptor channel proteins may be the primary one . Changes in the set of molecular subunits of which the channels are compos ed are also important, especially for long-term regulation. In the central nervous system synaptic plasticity may be altered by modulating the ligand- activated neuronal ion channels involved in synaptic transmission; among th em are channels gated directly by glutamate, the regulation of which we are only beginning to understand. This paper focuses on modulation of these ch annels [alpha-amino-3-hydroxy-5-methyl-4-isoxazoleprionic acid (AMPA), kain ate, and N-methyl-D-aspartate (NMDA) types] by phosphorylation and changes in subunit composition. AMPA- and kainate-activated receptors are modulated by adenosine 3, 5-monophosphate (cAMP) dependent protein kinase A (PKA) co upled via D-1 dopamine receptors. An increase in the intracellular concentr ation of cAMP and protein kinase A potentiates kainate-activated currents i n cu-motoneurons of the spinal cord by increasing the affinity of the ligan d (glutamate) for the phosphorylated receptor protein (GluR6 and 7). The ra pid desensitization of AMPA-evoked currents normally observed in horizontal cells of the retina is completely blocked by increasing the intracellular concentration of cAMP. The effects of changes in subunit composition were e xamined in rat hippocampal neurons. The subunit composition of the NMDA rec eptor determines the kinetic properties of synaptic currents and can be reg ulated by the type of innervating neuron. Similar changes also occur during development. An important determinant here is the activity of the system. Dynamic regulation of excitatory receptors by both mechanisms may well be a ssociated with some forms of learning and memory in the mammalian brain.