Receptor specific crosstalk and modulation of signaling upon heterodimerization between β1-adrenergic receptor and somatostatin receptor-5.
In the present study we describe heterodimerization, trafficking, coupling to adenylyl cyclase and signaling in HEK-293 cells cotransfected with human-somatostatin receptor 5 (hSSTR5) and β(1)-adrenergic receptor (β(1)AR). hSSTR5/β(1)AR exists as heterodimers in basal conditions which was further enhanced upon synergistic activation of both receptors. Activation of either β(1)AR or hSSTR5 displayed dissociation of heterodimerization. In cotransfectants, β(1)AR effect on cAMP was predominant; however, blocking β(1)AR with antagonist resulted in 60% inhibition of forskolin-stimulated cAMP in the presence of hSSTR5 agonists. cAMP/PKA pathway in cotransfected cells was regulated in receptor-specific manner, in contrast, the status of pERK1/2 and pPI3K/AKT was predominantly regulated by hSSTR5. The expression levels of phosphorylated NFAT remained unchanged indicating blockade of calcineurin-mediated dephosphorylation and nuclear translocation of NFAT, the process predominantly regulated by pJNK in SSTR5 dependent manner. Taken together, the functional consequences of results described here might have relevance in the cardiovascular system where SSTR and AR subtypes play important roles.
Faculty of Pharmaceutical Sciences, Division of Pharmacology and Toxicology, The University of British Columbia, Vancouver, BC, Canada.
Rishi K
RK
Somvanshi
Sajad A
SA
War
Nicole
N
Chaudhari
Xiaofan
X
Qiu
Ujendra
U
Kumar
D019703:Calcineurin / Q000378:metabolism; D002450:Cell Communication; D002460:Cell Line; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D019281:Dimerization; D006801:Humans; D007545:Isoproterenol / Q000494:pharmacology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D020239:Receptor Cross-Talk; D018342:Receptors, Adrenergic, beta-1 / Q000737:chemistry / Q000378:metabolism* / Q000502:physiology; D017481:Receptors, Somatostatin / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology; D015398:Signal Transduction; D013004:Somatostatin / Q000494:pharmacology
D050778:NFATC Transcription Factors; D018342:Receptors, Adrenergic, beta-1; D017481:Receptors, Somatostatin; D005576:Colforsin; D013004:Somatostatin; C094573:somatostatin receptor 5; D000242:Cyclic AMP; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D019703:Calcineurin; D007545:Isoproterenol