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Chronic Activation of Muscarinic and Metabotropic Glutamate Receptors Down‐Regulates Type I Inositol 1,4,5‐Trisphosphate Receptor Expression in Cerebellar Granule Cells
Author(s) -
Simpson Peter B.,
Challiss R. A. John,
Nahorski Stefan R.
Publication year - 1994
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.1994.63062369.x
Subject(s) - metabotropic receptor , receptor , metabotropic glutamate receptor , inositol phosphate , medicine , agonist , endocrinology , glutamate receptor , biology , inositol , stimulation , carbachol , receptor expression , granule cell , chemistry , biochemistry , hippocampal formation , dentate gyrus
The ability of receptors coupled to phosphoinositide turnover to evoke accumulation of inositol 1,4,5‐trisphosphate (InsP 3 ) over extended incubation periods, and consequently to affect the level of InsP 3 receptor expression, was studied in cultured cerebellar granule cells. The cholinergic agonist carbachol (CCh; 1 m M ) evoked a biphasic accumulation of InsP 3 , a rapid three‐ to fourfold peak increase over control levels at ∼10 s, decreasing within 1 min to a long‐lasting plateau elevation. Using an antibody against the type I InsP 3 receptor, it was demonstrated that >50% down‐regulation of type I InsP 3 receptor expression in cerebellar granule cells occurred within 1 h of incubation with 1 m M CCh. Over 24 h, 1 m M CCh caused an ∼85% decrease in type I InsP 3 receptor levels, and significant decreases in immunoreactivity were evident at much lower concentrations of CCh. Direct assessment of total InsP 3 receptor expression using a radioligand binding method also detected down‐regulation, but to an apparently lesser extent. 1‐Aminocyclopentane‐1 S ,3 R ‐dicarboxylic acid (200 µ M ), an agonist of metabotropic glutamate receptors, evoked a marked decrease in type I InsP 3 receptors after 24 h of incubation. These findings demonstrate that a functional consequence of maintained InsP 3 production in cerebellar granule cells is the down‐regulation of InsP 3 receptor expression and that this down‐regulation may be a common mechanism of action of phosphoinositide‐linked receptors during prolonged stimulation.