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Published on: April 24, 2012
Somatostatin receptor-2 negatively regulates β-adrenergic receptor mediated Ca(2+) dependent signaling pathways in
Rishi K Somvanshi1, Shenglong Zou1, Xiaofan Qiu1
1Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, BC V6T1Z3, Canada.
Abstract:
In the present study, we report that somatostatin receptor 2 (SSTR2) plays a crucial role in modulation of β1AR and β2AR mediated signaling pathways that are associated with increased intracellular Ca(2+) and cardiac complications. In H9c2 cells, SSTR2 colocalizes with β1AR or β2AR in receptor specific manner. SSTR2 selective agonist inhibits isoproterenol and formoterol stimulated cAMP formation and PKA phosphorylation in concentration dependent manner. In the presence of SSTR2 agonist, the expression of PKCα and PKCβ was comparable to the basal condition, however SSTR2 agonist inhibits isoproterenol or formoterol induced PKCα and PKCβ expression, respectively. Furthermore, the activation of SSTR2 not only inhibits calcineurin expression and its activity, but also blocks NFAT dephosphorylation and its nuclear translocation. SSTR2 selective agonist abrogates isoproterenol mediated increase in cell size and protein content (an index of hypertrophy). Taken together, the results described here provide direct evidence in support of cardiac protective role of SSTR2 via modulation of Ca(2+) associated signaling pathways attributed to cardiac hypertrophy.
Insights
Somatostatin receptor 2 (SSTR2) protects the heart by regulating calcium signaling pathways. This receptor modulates beta-adrenergic receptor (β-AR) activity, preventing cardiac hypertrophy and complications.
Area of Science:
- Cardiology
- Molecular Biology
- Pharmacology
Background:
- Beta-adrenergic receptors (β-ARs) mediate cardiac function but their overactivation can lead to hypertrophy.
- Intracellular calcium (Ca2+) signaling is critical in cardiac function and hypertrophy.
- Somatostatin receptor 2 (SSTR2) role in cardiac signaling is not fully understood.
Purpose of the Study:
- To investigate the role of SSTR2 in modulating β-AR signaling pathways.
- To determine if SSTR2 activation impacts Ca2+ handling and cardiac hypertrophy.
Main Methods:
- Utilized H9c2 cells to study receptor interactions and signaling.
- Administered SSTR2 selective agonists and β-AR agonists (isoproterenol, formoterol).
- Assessed cAMP formation, protein kinase A (PKA) phosphorylation, protein kinase C (PKC) expression, calcineurin activity, NFAT translocation, and cellular hypertrophy markers.
Main Results:
- SSTR2 colocalizes with β1AR and β2AR in H9c2 cells.
- SSTR2 activation inhibited isoproterenol/formoterol-induced cAMP production, PKA phosphorylation, and PKC expression.
- SSTR2 activation suppressed calcineurin/NFAT signaling and prevented isoproterenol-induced cardiac hypertrophy.
Conclusions:
- SSTR2 plays a significant role in modulating β-AR mediated signaling pathways.
- SSTR2 activation demonstrates a protective effect against cardiac hypertrophy by regulating Ca2+ signaling.
- SSTR2 represents a potential therapeutic target for managing cardiac hypertrophy.
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