Differential long-term regulation of TAS2R14 by structurally distinct agonists

Article

关键词: AIRWAY SMOOTH-MUSCLE;    BITTER TASTE RECEPTORS;    BETA(2)-ADRENERGIC RECEPTORS;    SWISS-MODEL;    DESENSITIZATION;    ASTHMA;    BRONCHODILATORS;    EXPRESSION;    DOCKING;   

DOI  :  10.1096/fj.201802627RR

来源: SCIE

【 摘 要 】

Bitter taste receptor-14 (TAS2R14) is a GPCR also expressed on human airway smooth muscle cells, which signals to intracellular [Ca2+], resulting in relaxation of the airway, and is a novel target for bronchodilators. Here, we examine long-term, agonist-promoted down-regulation of TAS2R14 expression because tachyphylaxis would be an undesirable therapeutic characteristic. Five TAS2R structurally distinct full agonists were studied to ascertain biasing away from down-regulation. Agonist exposure for 18 h caused minimal desensitization by diphenhydramine (DPD) compared with similar to 50% desensitization with all other agonists. Agonists evoked beta-arrestin recruitment to TAS2R14, which was not seen with a phosphoacceptor-deficient mutant, TAS2R14-10A. All agonists except for DPD also caused subsequent TAS2R14 internalization and trafficking via early and late endosomes to down-regulation. TAS2R14-10A failed to undergo these events with any agonist. Molecular docking showed that DPD has specific interactions deep within a binding pocket that are not observed with the other agonists, which may lock the receptor in a conformation that does not internalize and therefore does not undergo down-regulation. Thus, TAS2R14 is subject to beta-arrestin-mediated internalization and subsequent down-regulation with chronic exposure to most agonists. However, by manipulating the agonist structure, biasing toward G-protein coupling but away from long-term down-regulation can be achieved.

【 授权许可】

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