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CONCEPTION ET CARACTERISATION DE BIOCAPTEURS BASES SUR L'ASSOCIATION DE RECEPTEURS ET CANAUX IONIQUES

Abstract : ATP sensitive potassium channels (KATP) comprise two proteins: The sulfonylurea receptor (SUR, an ABC protein) and an inward rectifier potassium channel (Kir6.2). Upon binding of different types of effectors (nucleotides, pharmacological compounds), SUR, the regulatory subunit, modulates the gating of Kir6.2. The KATP channel links the metabolic state of the cell to its electrical excitability. Thereby, it acts as a metabolic sensor and is involved in physiological functions such as insulin secretion, cardioprotection, vascular tone control... Thus, the KATP channel constitutes a therapeutic target. In this work, we studied the effects of benzothiazine derivatives on SUR1 + Kir6.2 and SUR2A + Kir6.2. We also investigated the effects of two pesticides, amitraz and diflubenzuron on the KATP channel. To extend the concept of Ion Channel-Coupled Receptor (ICCR) initiated in the laboratory, we designed new constructs by engineering fusion between Kir6.2 and five GPCRs: the β2 adrenergic, cannabinoid 1 (CB1), dopaminergic D3, CC-chemokine (CCR2) receptors and opsin. The receptor C-ter and Kir6.2 N-ter extremities were pared to promote efficient coupling and joined covalently. The fusions were heterologously expressed in Xenopus oocytes and characterized by the two-electrode voltage clamp technique. Three ICCR β2 adrenergic-based, CB1-based and D3-based) out of five were shown to be functional. Thus, the ICCR concept is readily applicable to class A GPCRs. Besides their obvious interest in drug screening, the new ICCRs should be valuable tools to investigate the intermolecular events involved in the modulation of Kir6.2 gating and the nature of the GPCR conformational changes evoked by their ligands.
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https://tel.archives-ouvertes.fr/tel-00544513
Contributor : Lydia Caro <>
Submitted on : Wednesday, December 8, 2010 - 12:03:15 PM
Last modification on : Wednesday, November 4, 2020 - 2:12:25 PM
Long-term archiving on: : Saturday, December 3, 2016 - 3:51:58 AM

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  • HAL Id : tel-00544513, version 1

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Lydia Caro. CONCEPTION ET CARACTERISATION DE BIOCAPTEURS BASES SUR L'ASSOCIATION DE RECEPTEURS ET CANAUX IONIQUES. Sciences du Vivant [q-bio]. Université Joseph-Fourier - Grenoble I, 2010. Français. ⟨tel-00544513⟩

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