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Cooperativity between inhibition of cytosolic K+ efflux and AMPK activation during suppression of hypoxia-induced cellular apoptosis.
Gopalani, Nomesh K; Meena, Ram Niwas; Prasad, Dipti N; Ilavazhagan, Govindaswamy; Sharma, Manish.
Affiliation
  • Gopalani NK; Peptide and Proteomics Division, Defence Institute of Physiology and Allied Sciences (DIPAS), DRDO, Delhi, India.
Int J Biochem Cell Biol ; 44(1): 211-23, 2012 Jan.
Article in En | MEDLINE | ID: mdl-22064248
Cellular potassium homeostasis has recently emerged as a critical regulator of apoptosis in response to variety of stimuli. However, functional hierarchy of this phenomenon in the apoptotic cascade and therefore, its significance as a pathway for intervention is not fully established. Chronic hypoxia, a known threat to cell survival, also modulates cellular potassium homeostasis. In this study, we tested if hypoxia-induced apoptosis in lymphocytes can be prevented by modulating cellular K+ homeostasis. We observed that chronic hypoxia accelerated the rate of apoptosis in resting murine splenocytes concomitant with cytosolic K+ efflux. We tested several modalities including elevated extracellular potassium besides various K+ channel inhibitors to curtail hypoxia-induced K+ efflux and interestingly, established that the supplementation of KCl in extracellular medium was most effective in preventing hypoxia-induced apoptosis in these cells. Subsequent mechanistic dissection of pathways underlying this phenomenon revealed that besides effectively inhibiting hypoxia-induced efflux of K+ ion and its downstream cell-physiological consequences; elevated extracellular KCl modulated steady state levels of cellular ATP and culminated in stabilization of AMPKα with pro-survival consequences. Also, interestingly, global gene expression profiling revealed that KCl supplementation down regulated a distinct p53-regulated cellular sub-network of genes involved in regulation of DNA replication. Additionally, we present experimental evidence for the functional role of AMPK and p53 activation during suppression of hypoxia-induced apoptosis. In conclusion, our study highlights a novel bimodal effect wherein cooperativity between restoration of K+ homeostasis and a sustainable 'metabolic quiescence' induced by AMPK activation appeared indispensible for curtailing hypoxia-induced apoptosis.
Subject(s)

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Potassium / AMP-Activated Protein Kinases Limits: Animals Language: En Journal: Int J Biochem Cell Biol Journal subject: BIOQUIMICA Year: 2012 Document type: Article Affiliation country: India Country of publication: Países Bajos

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Potassium / AMP-Activated Protein Kinases Limits: Animals Language: En Journal: Int J Biochem Cell Biol Journal subject: BIOQUIMICA Year: 2012 Document type: Article Affiliation country: India Country of publication: Países Bajos