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

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

Address all correspondence and requests for reprints to: Gaetan Guillemette, Ph.D., Department of Pharmacology, Faculty of Medicine, Université de Sherbrooke, 3001, 12th Avenue North, Sherbrooke, Quebec, Canada J1H 5N4. 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-human embryonic kidney 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 wild-type 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 G_q 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.

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