Abstracts
Résumé
La phosphorylation d’un récepteur couplé aux protéines G (RCPG) par une kinase spécifique, nommée GRK (G protein-coupled receptor kinase), est une première étape qui participe, avec l’action des arrestines, à l’arrêt de la transmission du signal, au cours d’un processus appelé désensibilisation. Le dérèglement de ce mécanisme de protection cellulaire, mis en évidence dans différentes situations pathologiques, relève soit de mutations génétiques d’une GRK ou d’une arrestine, soit d’une variation de leur expression. Ce dérèglement a pour conséquence de modifier l’activité des RCPG qui interviennent dans de nombreuses fonctions vitales de l’organisme. Ainsi, dans la maladie d’Oguchi, la stimulation excessive de la rhodopsine par la lumière, due à la perte de fonction de la GRK1 ou de l’arrestine 1, conduit à des problèmes d’adaptation de la vision à l’obscurité. La mise au point d’un modèle de souris hypertendues, après transfection ciblée du gène de la GRK2 au niveau des vaisseaux, suggère fortement que l’augmentation de cette GRK participe, chez l’homme, au développement de l’hypertension associée à une baisse de l’effet vasodilatateur des récepteurs β-adrénergiques. L’idée de rétablir une activité RCPG normale en agissant sur ces mécanismes de désensibilisation a été couronnée de succès dans des modèles animaux de défaillance cardiaque chronique, et laisse supposer que la modulation de l’activité des GRK ou de la fonction des arrestines pourrait constituer une piste thérapeutique. Cependant, la réalisation d’essais chez l’homme devra encore attendre la découverte de molécules pharmacologiques efficaces et non toxiques.
Summary
Phosphorylation of the agonist-activated form of G-protein-coupled receptors (GPCRs) by a protein kinase from the G-protein-coupled receptor kinase (GRK) family initiates, with arrestin proteins, a negative feedback process known as desensitization. Because these receptors are involved in so many vital functions, it seems likely that disorders affecting GRK- or arrestin-mediated regulation of GPCRs would contribute to, if not engender, disease. Traditionally, it is believed that the desensitization process protects the cell against an overstimulation; however, in certain situations, this process is maladjusted and participes in disease progression. For example, in Oguchi disease, excessive rhodopsin stimulation due to a functional loss of GRK1 or arrestin 1 leads to light sensitization and stationary night blindness. Also, transgenic mice with vascular smooth muscle-targeted overexpression of GRK2 showed an elevated resting blood pressure, suggesting that increase in GRK2 level in humans is involved in hypertension associated with a decreased effect of β-adrenergic receptor-mediated vasorelaxation. The restoration of normal GPCR function in modulating the desensitization process has been successfully demonstrated in animal models of heart failure, which indicates that targeting GRKs or arrestins may open a novel therapeutic strategy in human diseases with GPCR dysregulation. However, the few effective pharmacological compounds in this domain currently preclude human clinical tests.
Appendices
Références
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