C-tail mediated modulation of somatostatin receptor type-4 homo- and heterodimerizations and signaling |
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Authors: | Rishi K Somvanshi Sabina Billova Geetanjali Kharmate Padmesh S Rajput Ujendra Kumar |
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Institution: | 1. Laboratory of Toxicology, Department of Pharmaceutical Sciences, KU Leuven, Campus Gasthuisberg O&N2, Herestraat 49 Box 922, B-3000 Leuven, Belgium;2. Biomedical Research Institute, Hasselt University and transnational University Limburg, Agoralaan Gebouw C, B-3590 Diepenbeek, Belgium;3. Laboratory of Cell Metabolism, Department of Pharmaceutical Sciences, KU Leuven, Campus Gasthuisberg O&N2, Herestraat 49 Box 823, B-3000 Leuven, Belgium |
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Abstract: | Somatostatin receptors show great diversity in response to agonist mediated receptor-specific homo- and heterodimerizations. Here, using photobleaching-fluorescence resonance energy transfer, immunocytochemistry, western blot and co-immunoprecipitation, we investigated dimerization, trafficking, coupling to adenylyl cyclase and signaling of human somatostatin receptor-4 (hSSTR4) in HEK-293 cells. We also determined the role of the C-tail of hSSTR4 on physiological responses of the cells. wt-hSSTR4 exogenously expressed in HEK-293 cells exhibits constitutive dimerization, inhibits forskolin-stimulated cAMP, and displays agonist dependent changes in pERK1/2 and pERK5 expressions. Upon C-tail deletion, the receptor loses membrane expression and ability to dimerize and inhibition of cAMP and pERK5 however, displays several-fold increases in the expression of pERK1/2. Chimeric hSSTR4 with the C-tail of hSSTR5 functions like wt-hSSTR4, in contrast, with the C-tail of hSSTR1 functions like C-tail deleted hSSTR4. hSSTR4 dimerization and signaling are associated with increased cyclin-dependent-kinase p27kip1 expression and inhibition of the cell proliferation. We also report heterodimerization between hSSTR4/hSSTR5, but not between hSSTR4/hSSTR1, with significant changes in receptor functions. Taken together, these data define a novel mechanism for the role of hSSTR4 in cell proliferation and modulation of signaling pathways. |
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