Regulation of Serotonin 1B Receptor by Glycogen Synthase Kinase-3. Export

@article{citeulike:5834504, abstract = {In response to 5-HT, the type 1 serotonin receptors (5-HT1Rs) preferentially couple to the inhibitory G protein and elicit many physiological and behavioral processes. However, their regulation by intracellular protein kinases has not been fully investigated. In this study, we identified that glycogen synthase kinase-3 (GSK3) selectively regulates 5-HT1Rs. In receptor-expressing cells and brain slices, activation of both 5-HT1AR and 5-HT1BR reduced forskolin-stimulated cAMP production, but only the effect of 5-HT1BR was abolished by selective GSK3 inhibitors, deletion of GSK3beta by RNAi, or overexpression of impaired GSK3beta mutants (R96A and K85,86A). A consensus GSK3 phosphorylation sequence was identified between the serine-154 and threonine-158 in the second intracellular loop of 5-HT1BR. Mutation of either serine-154 or threonine-158 to alanine significantly reduced response of 5-HT1BR to 5-HT. Active GSK3beta interacted with resting 5-HT1BR to form a protein complex. The interaction was enhanced by receptor activation, abolished by GSK3 inhibitors, and dependent on the phosphorylation state of serine-154. In addition, regulation of 5-HT1BR by GSK3 changed the dynamics of agonist-induced cell surface receptor internalization, in which lack of phosphorylation at S154 resulted in sustained reduction of 5-HT1BR at cell surface. Although the physiological consequences of selective regulation of 5-HT1BR by GSK3 remain to be identified, findings in this study reveal a new function of GSK3 as a protein kinase that is able to selectively regulate G protein-coupled receptors.}, author = {Chen, Ligong and Salinas, Gregory D. and Li, Xiaohua}, citeulike-article-id = {5834504}, citeulike-linkout-0 = {http://dx.doi.org/10.1124/mol.109.056994}, citeulike-linkout-1 = {http://view.ncbi.nlm.nih.gov/pubmed/19741007}, citeulike-linkout-2 = {http://www.hubmed.org/display.cgi?uids=19741007}, day = {9}, doi = {10.1124/mol.109.056994}, issn = {1521-0111}, journal = {Molecular pharmacology}, keywords = {5-htreceptor}, month = {September}, posted-at = {2009-09-24 02:43:32}, priority = {0}, title = {Regulation of Serotonin 1B Receptor by Glycogen Synthase Kinase-3.}, url = {http://dx.doi.org/10.1124/mol.109.056994}, year = {2009} }

TY - JOUR ID - citeulike:5834504 L3 - citeulike-article-id:5834504 N2 - In response to 5-HT, the type 1 serotonin receptors (5-HT1Rs) preferentially couple to the inhibitory G protein and elicit many physiological and behavioral processes. However, their regulation by intracellular protein kinases has not been fully investigated. In this study, we identified that glycogen synthase kinase-3 (GSK3) selectively regulates 5-HT1Rs. In receptor-expressing cells and brain slices, activation of both 5-HT1AR and 5-HT1BR reduced forskolin-stimulated cAMP production, but only the effect of 5-HT1BR was abolished by selective GSK3 inhibitors, deletion of GSK3beta by RNAi, or overexpression of impaired GSK3beta mutants (R96A and K85,86A). A consensus GSK3 phosphorylation sequence was identified between the serine-154 and threonine-158 in the second intracellular loop of 5-HT1BR. Mutation of either serine-154 or threonine-158 to alanine significantly reduced response of 5-HT1BR to 5-HT. Active GSK3beta interacted with resting 5-HT1BR to form a protein complex. The interaction was enhanced by receptor activation, abolished by GSK3 inhibitors, and dependent on the phosphorylation state of serine-154. In addition, regulation of 5-HT1BR by GSK3 changed the dynamics of agonist-induced cell surface receptor internalization, in which lack of phosphorylation at S154 resulted in sustained reduction of 5-HT1BR at cell surface. Although the physiological consequences of selective regulation of 5-HT1BR by GSK3 remain to be identified, findings in this study reveal a new function of GSK3 as a protein kinase that is able to selectively regulate G protein-coupled receptors. JF - Molecular pharmacology SN - 1521-0111 TI - Regulation of Serotonin 1B Receptor by Glycogen Synthase Kinase-3. KW - 5-htreceptor AU - Chen, Ligong AU - Salinas, Gregory AU - Li, Xiaohua PY - 2009/09/09/ UR - http://dx.doi.org/10.1124/mol.109.056994 ER -