Premium
Gα s sensitizes human SH‐SY5Y cells to apoptosis independently of the protein kinase A pathway
Author(s) -
Zhao Chunnian,
Lai Justin S.,
Warsh Jerry J.,
Li Peter P.
Publication year - 2006
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/jnr.20875
Subject(s) - sh sy5y , apoptosis , microbiology and biotechnology , chemistry , protein kinase a , kinase , biology , biochemistry , cell culture , genetics , neuroblastoma
Disturbances in Gα s‐L levels and function have been implicated in the pathophysiology of bipolar disorder, but the role of these changes in the development of the illness is not clear. In view of the critical role of Gα s ‐mediated cAMP signaling in regulating cell survival, we investigated the potential role of Gα s‐L in modulating susceptibility to cellular stressors in human SH‐SY5Y neuroblastoma cells. Overexpression of Gα s‐L to a level twice that of the vector‐transfected cells did not directly affect cell viability but significantly increased the sensitivity to induction of cell death by serum deprivation and other apoptotic stimuli, including staurosporine, H 2 O 2 , and tunicamycin. This enhanced sensitivity was associated with increased caspase‐3 activation and appearance of fragmented nuclei (Hoechst 33342 staining). The broad‐spectrum caspase inhibitor z‐VAD‐fmk completely suppressed cell death evoked by these apoptotic insults in both vector‐transfected and Gα s‐L ‐overexpressing cells. The increased vulnerability conferred by increased Gα s‐L expression was neither mimicked by cAMP analogs 8‐Br‐cAMP, 8‐CPT‐cAMP, and 8‐CPT‐2Me‐cAMP nor attenuated by PKA inhibitors Rp‐cAMPS and KT5720. These data indicate that Gα s‐L may modulate apoptotic processes in a caspase‐dependent manner through a signaling cascade that is independent of the cAMP/PKA or cAMP/Epac pathway. These results suggest that enhanced Gα s‐L expression, as was observed in post‐mortem brain of bipolar patients, may impair cellular resilience in response to intracellular stress signals resulting from mitochondrial and/or endoplasmic reticulum dysfunction implicated in this disorder. © 2006 Wiley‐Liss, Inc.