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Vol. 300, Issue 2, 468-477, February 2002
Department of Pharmacology, University of Texas Health Science
Center, San Antonio, Texas
We have examined the cellular processes underlying the desensitization
of the 5-hydroxytryptamine (5-HT)2A receptor induced by
agonist or antagonist exposure. Treatment of C6 glioma cells with
either 5-HT or the 5-HT2A receptor antagonist ketanserin resulted in an attenuation in 5-HT2A receptor function,
specifically the accumulation of inositol phosphates stimulated
by the partial agonist quipazine. 5-HT-induced desensitization of the
5-HT2A receptor involved receptor internalization through a
clathrin- and dynamin-dependent process because it was prevented by
concanavalin A, monodansylcadaverine, and by expression of the dominant
negative mutants 
-arrestin (319-418) and dynamin K44A. Although
short-term (i.e., 10 min) 5-HT and ketanserin exposure resulted in the
same degree of desensitization, ketanserin-induced desensitization was
not prevented by these agents and did not involve receptor internalization. In contrast, prolonged ketanserin exposure (i.e., 2 h) resulted in 5-HT2A receptor internalization
through a clathrin- and dynamin-dependent process, as was observed
after agonist treatment. Inhibitors of protein kinase C or
calcium-calmodulin kinase II did not attenuate or prevent 5-HT-induced
desensitization of the receptor. 5-HT2A receptor
desensitization induced by 5-HT and prolonged ketanserin treatment, but
not by short-term ketanserin treatment, was prevented by the expression
of the dominant negative mutant of G protein-coupled receptor kinase
(GRK)2, GRK2-K220R, and by an anti-GRK2/3 antibody. Our data indicate a
dual mechanism of early and late desensitization by the antagonist
ketanserin. Short-term ketanserin treatment reduced the specific
binding of the agonist radioligand
[125I](±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane
([125I]DOI) and the ability of
5'-guanylylimidodiphosphate to attenuate this binding, suggesting that
at the early stage of antagonist-induced desensitization the capacity
of the 5-HT2A receptor to couple to G protein is impaired.
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