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A Small Sequence in the Third Intracellular Loop of the VPAC₁ Receptor Is Responsible for Its Efficient Coupling to the Calcium Effector

Department of Biological Chemistry and Nutrition, Faculty of Medicine, Université Libre de Bruxelles, B-1070 Brussels, Belgium

Address all correspondence and requests for reprints to: Dr. Ingrid Langer, Department of Biological Chemistry and Nutrition, Université Libre de Bruxelles, Faculty of Medicine, Bat GE, CP 611, 808 Route de Lennik, B-1070 Brussels, Belgium. E-mail: ilanger{at}ulb.ac.be.

The stimulatory effect of VIP on intracellular calcium concentration ([Ca²⁺]_i) has been investigated in Chinese hamster ovary cells stably transfected with the reporter gene aequorin, and expressing human VPAC₁, VPAC₂, chimeric VPAC₁/VPAC₂, or mutated receptors. The VIP-induced [Ca²⁺]_i increase was linearly correlated with receptor density and was higher in cells expressing VPAC₁ receptors than in cells expressing a similar VPAC₂ receptor density. The study was performed to establish the receptor sequence responsible for that difference. VPAC₁/VPAC₂ chimeric receptors were first used for a broad positioning: those having the third intracellular loop (IC₃) of the VPAC₁ or of the VPAC₂ receptor behaved, in that respect, phenotypically like VPAC₁ and VPAC₂ receptor, respectively. Replacement in the VPAC₂ receptor of the sequence 315–318 (VGGN) within the IC₃ by its VPAC₁ receptor counterpart 328–331 (IRKS) and the introduction of VGGN in state of IRKS in VPAC₁ was sufficient to mimic the VPAC₁ and VPAC₂ receptor characteristics, respectively.

Thus, a small sequence in the IC₃ of the VPAC₁ receptor, probably through interaction with G_i and G_q proteins, is responsible for the efficient agonist-stimulated [Ca²⁺]_i increase.

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