摘要：G protein-coupled receptors(GPCRs)convert extracellular stimuli in the form of hormones,odorants and light into profound changes in cell *** timely desensitization is critical for cells to rapidly respond to changes in their environment and to avoid damage from sustained *** GPCR kinases(GRKs)phosphorylate and regulate the activity of most of the^800 GPCRs in the human *** GRKs normally play an adaptive role,in conditions such as chronic heart failure they are overexpressed and linked to disease ***2 and GRK5 have thus become important targets for the treatment of heart failure and pathological cardiac hypertrophy,*** lab has determined atomic structures representing all three vertebrate GRK subfamilies,and is now in the midst of a campaign to develop selective inhibitors of these enzymes using structure-based rational *** have identified the FDA approved drug paroxetine as a selective GRK2 inhibitor,determined the crystal structure of the GRK2·paroxetine complex and,in collaboration with the Koch lab,showed that the drug improves contractility in myocytes and,most impressively,recovery in postmyocardial infarcted *** then,we have identified additional chemical scaffolds that exhibit even higher potency and/or selectivity for *** a"hybrid"inhibitor design approach we have generated GRK selective chemical probes that exhibit improved potency and stability and are able to increase inotropy and dampen the hypertrophic response in cardiomyocytes and small animal *** analysis has revealed the molecular basis for selectivity and potency in many of these compounds,allowing for the design of future generations of GRK chemical probes.