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.