GABA(A) receptor modulation in rat cerebellum granule cells

Citation
A. Cupello et M. Robello, GABA(A) receptor modulation in rat cerebellum granule cells, RECEPT CHAN, 7(2), 2000, pp. 151-171
Citations number
200
Categorie Soggetti
Cell & Developmental Biology
Journal title
RECEPTORS & CHANNELS
ISSN journal
10606823 → ACNP
Volume
7
Issue
2
Year of publication
2000
Pages
151 - 171
Database
ISI
SICI code
1060-6823(2000)7:2<151:GRMIRC>2.0.ZU;2-X
Abstract
The inhibitory GABA(A) receptor is a key element in determining the pattern of nerve cell electrical activity, Thus, modulation of its function is of paramount impact in shaping neuronal functional activity under physiologica l and pathological conditions. This applies to cerebellar granule neurons a s to all the other neurons in the brain. The culture of cerebellar granules from newborn rats is a convenient means by which to approach these cells f or electrophysiological studies provided that they maintain, as far as GABA (A) receptors are concerned, the same characteristics as in situ. Thus, the regulation of GABA(A) receptor activity in these neurons has been studied by the patch-clamp technique, both in the whole-cell and outside-out config uration. An obvious first level of control of such receptors' activity is their dese nsitization under continued agonist application, with biphasic kinetics. Th e data do not allow one to conclude whether one is dealing with two differe nt populations of receptors or with a single population with two desensitiz ation phases: although the presence of two GABA(A) receptor populations is suggested by a host of observations. The granule cell GABA(A) receptors are modulated by changes in extracellula r pH with lower pn resulting ill an enhanced receptor activity. They displa y, under the conditions of whole-cell recording, a run-down phenomenon whic h is most probably due to a tyrosine phosphatase activity which is in turn under control by a protein serine kinase. Thus, in situ tyrosine phosphoryl ation is a key element in determining the efficiency of GABA mediated inhib ition, Activation of protein kinase A or protein kinase G (PKG) downregulat es GABA(A) rcceptors' activity. This last event is involved in the depressi on of those receptors' activity by L-arginine via the production of nitric oxide. In addition, the activity of calmodulin-activated adenylate cyclase I is controlled by GABA(B) receptors. Dendritic GABA(A) receptor activity is partially blocked by previous activa tion of N-methyl-D-aspartate (NMDA) receptors via calcineurin mediated deph osphorylation/activation of protein tyrosine phosphatase and concomitant pr oduction of nitric oxide and PKG activation, The site phosphorylated by PKG is evidently not available for calcineurin-mediated serine dephosphorylati on, due to calcineurin-specific membrane localization in respect of the GAB A(A) receptor. Overall, a complex network of biochemical signals appear to keep granule cells GABA(A) receptors under a fine balance between up- and d own-regulatory mechanisms. The overall data appear also to indicate the presence of two GABA(A) recept or populations: a dendritic one which can be modulated by Ca++ entering via NMDA receptors and a cell body one. The two populations are probably diffe rent in terms of desensitization kinetics and benzodiazepine sensitivity.