Gαi/o protein-coupled dopamine D3 receptors （D3Rs） are preferentially expressed in the limbic system, including the nucleus accumbens. This situates the receptor well in the regulation of limbic function and in the...Gαi/o protein-coupled dopamine D3 receptors （D3Rs） are preferentially expressed in the limbic system, including the nucleus accumbens. This situates the receptor well in the regulation of limbic function and in the pathogenesis of various neuropsychiatric and neurodegenerative disorders. The intracellular domains of the receptor, mainly the large third intracellular loop and the intracellular C-terminal tail, interact with multiple submembranous proteins. These interactions are critical for the control of surface expression of the receptor and the efficacy of receptor signaling. Recently, a synapse-enriched protein kinase, Ca^2＋/calmodulin-dependent protein kinase II （CaMKII）, has been found to interact with D3R in the above mentioned interaction model. CaMKII directly binds to the N-terminal of the third loop of D3R. This binding is Ca^2＋-dependent and is sustained by the autophosphorylation of the kinase. In rat accumbal neurons, the increase in Ca^2＋ level induces the recruitment of CaMKII to D3R, and CaMKII phosphorylates the receptor at a specific serine site. The CaMKII-induced phosphorylation could inhibit the receptor function and further regulate the behavioral response to the psychostimulant cocaine. These findings reveal a prototypic protein association model between a G protein-coupled receptor and CaMKII. Through the dynamic protein-protein interactions, the abundance, turnover cycle, and function of D3R can be regulated by multiple signals and enzymatic proteins.展开更多
Protein-protein interactions represent an important mechanism for posttranslational modifications of protein expression and function.In brain cells,surface-expressed and membrane-bound neurotransmitter receptors are c...Protein-protein interactions represent an important mechanism for posttranslational modifications of protein expression and function.In brain cells,surface-expressed and membrane-bound neurotransmitter receptors are common proteins that undergo dynamic protein-protein interactions between their intracellular domains and submembranous regulatory proteins.Recently,the Gφi/o -coupled muscarinic M4 receptor（M4R）has been revealed to be one of these receptors.Through direct interaction with the intracellular loops or C-terminal tails of M4Rs,M4R interacting proteins（M4RIPs）vigorously regulate the efficacy of M4R signaling.A synapse-enriched protein kinase,Ca2＋/calmodulin-dependent protein kinase II （CaMKII）,exemplifies a prototype model of M4RIPs,and is capable of binding to the second intracellular loop of M4Rs. Through an activity-and phosphorylation-dependent mechanism,CaMKII potentiates the M4R/Gφi/o-mediated inhibition of M4R efficacy in inhibiting adenylyl cyclase and cAMP production.In striatal neurons where M4Rs are most abundantly expressed,M4RIPs dynamically control M4R activity to maintain a proper cholinergic tone in these neurons.This is critical for maintaining the acetylcholine-dopamine balance in the basal ganglia,which determines the behavioral responsiveness to dopamine stimulation by psychostimulants.展开更多
基金supported by the grant from the Saint Luke’s Hospital Foundation (Kansas City, MO, USA)grants (No. R01-DA010355, R01-MH061469) from the National Institutes of Health (Bethesda,MD, USA)
文摘Gαi/o protein-coupled dopamine D3 receptors （D3Rs） are preferentially expressed in the limbic system, including the nucleus accumbens. This situates the receptor well in the regulation of limbic function and in the pathogenesis of various neuropsychiatric and neurodegenerative disorders. The intracellular domains of the receptor, mainly the large third intracellular loop and the intracellular C-terminal tail, interact with multiple submembranous proteins. These interactions are critical for the control of surface expression of the receptor and the efficacy of receptor signaling. Recently, a synapse-enriched protein kinase, Ca^2＋/calmodulin-dependent protein kinase II （CaMKII）, has been found to interact with D3R in the above mentioned interaction model. CaMKII directly binds to the N-terminal of the third loop of D3R. This binding is Ca^2＋-dependent and is sustained by the autophosphorylation of the kinase. In rat accumbal neurons, the increase in Ca^2＋ level induces the recruitment of CaMKII to D3R, and CaMKII phosphorylates the receptor at a specific serine site. The CaMKII-induced phosphorylation could inhibit the receptor function and further regulate the behavioral response to the psychostimulant cocaine. These findings reveal a prototypic protein association model between a G protein-coupled receptor and CaMKII. Through the dynamic protein-protein interactions, the abundance, turnover cycle, and function of D3R can be regulated by multiple signals and enzymatic proteins.
基金supported by thegrants from the Saint Luke’s Hospital Foundation(Kansas City,MO,USA)the National Institute of Health(Bethesda,MD,USA)(No.R01-DA010355-16,R01-MH061469-10)
文摘Protein-protein interactions represent an important mechanism for posttranslational modifications of protein expression and function.In brain cells,surface-expressed and membrane-bound neurotransmitter receptors are common proteins that undergo dynamic protein-protein interactions between their intracellular domains and submembranous regulatory proteins.Recently,the Gφi/o -coupled muscarinic M4 receptor（M4R）has been revealed to be one of these receptors.Through direct interaction with the intracellular loops or C-terminal tails of M4Rs,M4R interacting proteins（M4RIPs）vigorously regulate the efficacy of M4R signaling.A synapse-enriched protein kinase,Ca2＋/calmodulin-dependent protein kinase II （CaMKII）,exemplifies a prototype model of M4RIPs,and is capable of binding to the second intracellular loop of M4Rs. Through an activity-and phosphorylation-dependent mechanism,CaMKII potentiates the M4R/Gφi/o-mediated inhibition of M4R efficacy in inhibiting adenylyl cyclase and cAMP production.In striatal neurons where M4Rs are most abundantly expressed,M4RIPs dynamically control M4R activity to maintain a proper cholinergic tone in these neurons.This is critical for maintaining the acetylcholine-dopamine balance in the basal ganglia,which determines the behavioral responsiveness to dopamine stimulation by psychostimulants.
