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This version published online on August 26, 2004
Molecular Endocrinology, doi:10.1210/me.2003-0488
Molecular Endocrinology Vol. 0, No. 2004 200304881-
doi:10.1210/me.2003-0488
Copyright © 2004 by the Endocrine Society.
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Submitted on December 18, 2003
Accepted on August 18, 2004

Down-Regulation of Inositol 1,4,5-Trisphosphate Receptor in Cells Stably Expressing the Constitutively Active Angiotensin II N111G-AT1 Receptor

Mannix Auger-Messier, Guillaume Arguin, Benoit Chaloux, Richard Leduc, Emanuel Escher, and Gaetan Guillemette*

Department of Pharmacology, Faculty of Medicine, Université de Sherbrooke, Sherbrooke, Quebec, Canada, J1H 5N4

* To whom correspondence should be addressed. E-mail: Gaetan.Guillemette{at}USherbrooke.ca.

The diverse cellular changes brought about by the expression of a constitutively active receptor are poorly understood. QBI-HEK 293A cells stably expressing the constitutively active N111G-AT1 receptor (N111G cells) showed elevated levels of inositol phosphates and frequent spontaneous intracellular Ca2+ oscillations. Interestingly, Ca2+ transients triggered with maximal doses of angiotensin II were much weaker in N111G cells than in WT cells. These blunted responses were observed independently of the presence or absence of extracellular Ca2+ and were also obtained when endogenous muscarinic and purinergic receptors were activated, revealing a heterologous desensitization process. The desensitized component of the Ca2+ signaling cascade was neither the G protein Gq nor phospholipase C. The intracellular Ca2+ store of N111G cells and their mechanism of Ca2+ entry also appeared to be intact. The most striking adaptive response of N111G cells was a down-regulation of their inositol 1,4,5-trisphosphate receptor (IP3R) as revealed by reduced IP3-induced Ca2+ release, lowered [3H]IP3 binding capacity, diminished IP3R immunoreactivity and accelerated IP3R degradation involving the lysosomal pathway. Treatment with the inverse agonist EXP3174 reversed the desensitized phenotype of N111G cells. Down-regulation of IP3R represents a reversible adaptive response to protect cells against the adverse effects of constitutively active Ca2+-mobilizing receptors.
Key words: constitutively active mutant GPCR • IP3R down-regulation • desensitization • lysosomal degradation • adaptive process • inverse agonist




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