craig irving | University of Rhode Island (original) (raw)
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Istituto Italiano di Tecnologia / Italian Institute of Technology
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Papers by craig irving
The treatment of psychological diseases like schizophrenia has depended on the use of antipsychot... more The treatment of psychological diseases like schizophrenia has depended on the use of antipsychotic drugs many of which were created as far back as the 1970’s. These drugs typically act on the D2 dopamine receptor (D2R) to antagonize its signaling and alter the signaling of the mesolimbic and mesocortical dopaminergic pathways in the brain. Several studies have indicated that it may be more important to identify the specific receptor-protein interactions which could prove to be more beneficial drug targets for the treatment of schizophrenia (Magalhaes, Dunn, & Ferguson, 2012). In this study we identified that the fourth transmembrane motif in D2R is responsible for the receptor-protein interaction that was previously shown to decrease the detergent solubility of cellular Gβ5. Furthermore, we showed that the biophysical effects of this receptor-protein interaction could be significantly altered by treatment with clozapine but not haloperidol. Clozapine is a first generation antipsych...
Journal of Biological Chemistry
Most clinically available antipsychotic drugs (APDs) bind dopamine D2 receptors (D2R) at therapeu... more Most clinically available antipsychotic drugs (APDs) bind dopamine D2 receptors (D2R) at therapeutic concentrations, and it is thought that they suppress psychotic symptoms by serving as competitive antagonists of dopamine at D2R. Here, we present data that demonstrate that APDs act independently of dopamine at an intracellular pool of D2R to enhance transport of D2R to the cell surface and suggest that APDs can act as pharmacological chaperones at D2R. Among the first- and second-generation APDs that we tested, clozapine exhibited the lowest efficacy for translocating D2R to the cell surface. Thus, our observations could provide a cellular explanation for some of the distinct therapeutic characteristics of clozapine in schizophrenia. They also suggest that differential intracellular actions of APDs at their common G protein–coupled receptor (GPCR) target, D2R, could contribute to differences in their clinical profiles.
The treatment of psychological diseases like schizophrenia has depended on the use of antipsychot... more The treatment of psychological diseases like schizophrenia has depended on the use of antipsychotic drugs many of which were created as far back as the 1970’s. These drugs typically act on the D2 dopamine receptor (D2R) to antagonize its signaling and alter the signaling of the mesolimbic and mesocortical dopaminergic pathways in the brain. Several studies have indicated that it may be more important to identify the specific receptor-protein interactions which could prove to be more beneficial drug targets for the treatment of schizophrenia (Magalhaes, Dunn, & Ferguson, 2012). In this study we identified that the fourth transmembrane motif in D2R is responsible for the receptor-protein interaction that was previously shown to decrease the detergent solubility of cellular Gβ5. Furthermore, we showed that the biophysical effects of this receptor-protein interaction could be significantly altered by treatment with clozapine but not haloperidol. Clozapine is a first generation antipsych...
Journal of Biological Chemistry
Most clinically available antipsychotic drugs (APDs) bind dopamine D2 receptors (D2R) at therapeu... more Most clinically available antipsychotic drugs (APDs) bind dopamine D2 receptors (D2R) at therapeutic concentrations, and it is thought that they suppress psychotic symptoms by serving as competitive antagonists of dopamine at D2R. Here, we present data that demonstrate that APDs act independently of dopamine at an intracellular pool of D2R to enhance transport of D2R to the cell surface and suggest that APDs can act as pharmacological chaperones at D2R. Among the first- and second-generation APDs that we tested, clozapine exhibited the lowest efficacy for translocating D2R to the cell surface. Thus, our observations could provide a cellular explanation for some of the distinct therapeutic characteristics of clozapine in schizophrenia. They also suggest that differential intracellular actions of APDs at their common G protein–coupled receptor (GPCR) target, D2R, could contribute to differences in their clinical profiles.