C-tail mediated modulation of somatostatin receptor type-4 homo- and heterodimerizations and signaling.
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 p27(kip1) 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.
Somvanshi
Rishi K
RK
Faculty of Pharmaceutical Sciences, Division of Pharmacology and Toxicology, The University of British Columbia, BC, Canada.
Billova
Sabina
S
Kharmate
Geetanjali
G
Rajput
Padmesh S
PS
Kumar
Ujendra
U
D002460:Cell Line; D049109:Cell Proliferation; D019281:Dimerization; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D031541:Fluorescence Resonance Energy Transfer; D006801:Humans; D050505:Mutant Proteins / Q000378:metabolism / Q000502:physiology; D017434:Protein Structure, Tertiary; D017481:Receptors, Somatostatin / Q000737:chemistry / Q000378:metabolism* / Q000502:physiology; D015398:Signal Transduction
D050505:Mutant Proteins; D017481:Receptors, Somatostatin; C098681:somatostatin receptor subtype-4; C101130:somatostatin receptor type 1; C094573:somatostatin receptor 5; D048049:Extracellular Signal-Regulated MAP Kinases