Coexpression of human somatostatin receptor-2 (SSTR2) and SSTR3 modulates antiproliferative signaling and apoptosis

Journal of Molecular Signaling

Ujendra Kumar¹  Sajad A War¹ 

[1] Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, BC, V6T 1Z3, Canada

关键词: Somatostatin receptors;    Somatostatin;    Heterodimerization;    G protein-coupled receptor (GPCR);    Photobleaching-Fluorescence resonance energy transfer (Pb-FRET);    Apoptosis;   

Others  :  803052
DOI  :  10.1186/1750-2187-7-5

 received in 2011-11-25, accepted in 2012-05-31,  发布年份 2012

【 摘 要 】

Background

Somatostatin (SST) via five G_i coupled receptors namely SSTR1-5 is known to inhibit cell proliferation by cytostatic and cytotoxic mechanisms. Heterodimerization plays a crucial role in modulating the signal transduction pathways of SSTR subtypes. In the present study, we investigated human SSTR2/SSTR3 heterodimerization, internalization, MAPK signaling, cell proliferation and apoptosis in HEK-293 cells in response to SST and specific agonists for SSTR2 and SSTR3.

Results

Although in basal conditions, SSTR2 and SSTR3 colocalize at the plasma membrane and exhibit heterodimerization, the cell surface distribution of both receptors decreased upon agonist activation and was accompanied by a parallel increase in intracellular colocalization. Receptors activation by SST and specific agonists significantly decreased cAMP levels in cotransfected cells in comparison to control. Agonist-mediated modulation of pERK1/2 was time and concentration-dependent, and pronounced in serum-deprived conditions. pERK1/2 was inhibited in response to SST; conversely receptor-specific agonist treatment caused inhibition at lower concentration and activation at higher concentration. Strikingly, ERK1/2 phosphorylation was sustained upon prolonged treatment with SST but not with receptor-specific agonists. On the other hand, SST and receptor-specific agonists modulated p38 phosphorylation time-dependently. The receptor activation in cotransfected cells exhibits G_i-dependent inhibition of cell proliferation attributed to increased PARP-1 expression and TUNEL staining, whereas induction of p21 and p27^Kip1 suggests a cytostatic effect.

Conclusion

Our study provides new insights in SSTR2/SSTR3 mediated signaling which might help in better understanding of the molecular interactions involving SSTRs in tumor biology.

【 授权许可】

   
2012 War and Kumar; licensee BioMed Central Ltd.

【 图 表 】

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