Metabotropic Glutamate Responses and the Intracellular Mechanisms

Abstract

Glutamate and its analogs are the predominant excitatory neurotransmitters in the central nervous system (CNS). They are known to be critically involved in physiological and pathological processes such as learning, memory, and neuronal degeneration. Based on electrophysiological and pharmacological studies, the glutamate receptors are classified into (1) ionotropic receptors (iGluR), which are directly coupled with ionic channels and are subdivided into α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate/kainate (AMPA/KA) and N-methyl-D-aspartate (NMDA) receptors, and (2) metabotropic receptors (mGluR), which are coupled to either inositol-1,4,5-triphosphate (IP3)/Ca2+ or cyclic adenosine monophosphate (cAMP) pathways for signal transduction. The aim of the study was to clearly identify the electrophysiological responses to mGluR stimulation in CNS neurons and to compare them in different brain areas. To circumvent these problems, we used acutely dissociated rat CNS neurons and a quick drug-application system termed the Y-tube method. Detailed electrophysiological analysis was performed with the nystatin perforated patch recording mode, which prevents the washout of soluble intracellular substances during recording. Using this novel technique, mGluR responses could be recorded continuously for more than l h. We characterized the mGluR responses in seven regions of the rat brain. The responses were either activation of Ca2+-activated K+ current (IK(Ca)), M current (IM) suppression, leakage K+ current suppression, or a combination of these, depending on the brain regions to be studied. These results on the regional difference along with the antagonist studies indicate that there are multiple types of mGluR. Both IK(Ca) and IM are known to regulate the firing patterns of neurons and the amplitude of the postsynaptic potential. Moreover, the threshold concentration for mGluR response was 10–100 fold lower than that for iGluR response, indicating a wider range of operation. On the basis of these facts, we propose that mGluR is a finely tuned modulator of membrane excitability in the CNS.