title: Somatostatin receptor-3 mediated intracellular signaling and apoptosis is regulated by its cytoplasmic terminal.
abstract: In the present study, we describe the role of cytoplasmic terminal (C-tail) domain in regulating coupling to adenylyl cyclase, signaling, and apoptosis in human embryonic kidney (HEK-293) cells transfected with wild type (wt)-hSSTR3 and C-tail deleted mutants. Cells transfected with wt-hSSTR3 and C-tail mutants show comparable membrane expression; however, display decreased expression in presence of agonist. wt-hSSTR3 exists as preformed homodimer at cell surface in basal conditions and decreases in response to agonist. Cells expressing C-tail mutants also show evidence of homodimerization with the same intensity as wt-hSSTR3. The agonist-dependent inhibition of cyclic adenosine monophosphate (cAMP) was lost in cells expressing C-tail mutants. Agonist treatment in cells expressing wt-hSSTR3 resulted in inhibition of cell proliferation, increased expression of PARP-1, and TUNEL positivity in proliferating cell nuclear antigen (PCNA)-positive cells. The agonist mediated increase in membrane expression of protein tyrosine phosphatase (PTP) seen with wt-hSSTR3 was diminished in C-tail mutants, which was accompanied with the loss of receptor's ability to induce apoptosis. Taken together, our data provide new insights into C-tail-dependent regulation of cell signaling and apoptosis by hSSTR3.
authors.affiliation: Faculty of Pharmaceutical Sciences, Division of Pharmacology and Toxicology, The University of British Columbia, Vancouver, BC V6T1Z3, Canada.
authors.forename: Sajad A
authors.initials: SA
authors.lastname: War
authors.forename: Rishi K
authors.initials: RK
authors.lastname: Somvanshi
authors.forename: Ujendra
authors.initials: U
authors.lastname: Kumar
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism*; D000595:Amino Acid Sequence; D017209:Apoptosis; D002460:Cell Line; D049109:Cell Proliferation; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000378:metabolism; D017481:Receptors, Somatostatin / Q000819:agonists / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D015854:Up-Regulation
chemical_list: D017481:Receptors, Somatostatin; C103631:somatostatin receptor 3; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; C509249:PTPN6 protein, human; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D000262:Adenylyl Cyclases