G protein-coupled receptors(GPCRs)convert extracellular stimuli in the form of hormones,odorants and light into profound changes in cell homeostasis.Their timely desensitization is critical for cells to rapidly respon...G protein-coupled receptors(GPCRs)convert extracellular stimuli in the form of hormones,odorants and light into profound changes in cell homeostasis.Their timely desensitization is critical for cells to rapidly respond to changes in their environment and to avoid damage from sustained signaling.Seven GPCR kinases(GRKs)phosphorylate and regulate the activity of most of the^800 GPCRs in the human genome.Although GRKs normally play an adaptive role,in conditions such as chronic heart failure they are overexpressed and linked to disease progression.GRK2 and GRK5 have thus become important targets for the treatment of heart failure and pathological cardiac hypertrophy,respectively.Our 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 design.We 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 mice.Since then,we have identified additional chemical scaffolds that exhibit even higher potency and/or selectivity for GRK5.Using 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 models.Structural 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.展开更多
The function of lymphocytes is dependent on their plasticity,particularly their adaptation to energy availability and environmental stress,and their protein synthesis machinery.Lymphocytes are constantly under metabol...The function of lymphocytes is dependent on their plasticity,particularly their adaptation to energy availability and environmental stress,and their protein synthesis machinery.Lymphocytes are constantly under metabolic stress,and macroautophagy/autophagy is the primary metabolic pathway that helps cells overcome stressors.The intrinsic role of autophagy in regulating the metabolism of adaptive immune cells has recently gained increasing attention.In this review,we summarize and discuss the versatile roles of autophagy in regulating cellular metabolism and the implications of autophagy for immune cell function and fate,especially for T and B lymphocytes.展开更多
基金supported by National Institutes of Health(NIH)grants HL071818,HL086865,and HL122416(to JT)American Heart Association grant 15PRE22730028(to HW)+1 种基金JT and SL were supported by grants from the Center for Discovery of New Medicine,University of MichiganMCC and OC acknowledge training grant support from the University of Michigan Chemistry Biology Interface training program(NIH grant 5T32GM008597)
文摘G protein-coupled receptors(GPCRs)convert extracellular stimuli in the form of hormones,odorants and light into profound changes in cell homeostasis.Their timely desensitization is critical for cells to rapidly respond to changes in their environment and to avoid damage from sustained signaling.Seven GPCR kinases(GRKs)phosphorylate and regulate the activity of most of the^800 GPCRs in the human genome.Although GRKs normally play an adaptive role,in conditions such as chronic heart failure they are overexpressed and linked to disease progression.GRK2 and GRK5 have thus become important targets for the treatment of heart failure and pathological cardiac hypertrophy,respectively.Our 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 design.We 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 mice.Since then,we have identified additional chemical scaffolds that exhibit even higher potency and/or selectivity for GRK5.Using 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 models.Structural 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.
文摘The function of lymphocytes is dependent on their plasticity,particularly their adaptation to energy availability and environmental stress,and their protein synthesis machinery.Lymphocytes are constantly under metabolic stress,and macroautophagy/autophagy is the primary metabolic pathway that helps cells overcome stressors.The intrinsic role of autophagy in regulating the metabolism of adaptive immune cells has recently gained increasing attention.In this review,we summarize and discuss the versatile roles of autophagy in regulating cellular metabolism and the implications of autophagy for immune cell function and fate,especially for T and B lymphocytes.
