title: High-energy compounds mobilize intracellular Ca2+ and activate calpain in cultured cells: is calpain an energy-dependent protease?
abstract: Deficiency in energy metabolisms is perhaps the earliest modifiable defect in brain aging and sporadic Alzheimer's disease (sAD). Several high-energy compounds (HECs) such as ATP, phosphoenolpyruvate, phosphocreatine and acetyl coenzyme A have been shown to exhibit neuroprotective effects. To understand their mechanism of actions, we tested the effects of these HECs on intracellular Ca(2+), a central regulator in brain function. Our data showed that the HECs robustly and dose-dependently mobilized intracellular Ca(2+) in cultured SH-SY5Y cells, and the actions were sensitive to intracellular Ca(2+) chelator BAPTA-AM or energy metabolism blocker rotenone. The Ca(2+) influx triggered by the HECs was from both extracellular medium and intracellular stores and the HECs also induced repetitive Ca(2+) oscillations. As these actions were similar to those of classical Ca(2+) agonists, the HECs may be viewed as a new group of physiological Ca(2+) agonists. We also found that the HECs promoted the intracellular activity of calpain, a Ca(2+)-dependent protease, and the enzyme activity fluctuated in concert with cellular energy levels, suggesting that calpain activity may also be energy-driven or energy-dependent. These findings may add to current knowledge for the regulatory mechanisms of Ca(2+) and calpain. Since Ca(2+) and calpain undergo critical dysfunction in brain aging but the underlying mechanisms remain elusive, our work may provide a new perspective for clarifying some controversies. More importantly, the HECs, as key intermediates in glucose catabolism, the primary source of energy supply in the brain, may be used as potential drugs for rational prevention of sAD.
authors: Aging Research Laboratory, Bay Pines VA Healthcare System, Bay Pines, FL 33744, USA.
authors: Huey T
authors: HT
authors: Nguyen
authors: Aging Research Laboratory, Bay Pines VA Healthcare System, Bay Pines, FL 33744, USA; Department of Molecular Pharmacology and Physiology, University of South Florida, Tampa, FL, USA. Electronic address: ming.chen@va.gov.
authors: Ming
authors: M
authors: Chen
mesh_terms: D000105:Acetyl Coenzyme A / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000544:Alzheimer Disease / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D002154:Calpain / Q000378:metabolism*; D045744:Cell Line, Tumor; D002614:Chelating Agents / Q000494:pharmacology; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004151:Dipeptides / Q000494:pharmacology; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D005110:Extracellular Space / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism*; D009538:Nicotine / Q000494:pharmacology; D018722:Nicotinic Agonists / Q000494:pharmacology; D010725:Phosphocreatine / Q000378:metabolism; D010728:Phosphoenolpyruvate / Q000378:metabolism; D012402:Rotenone / Q000494:pharmacology; D014475:Uncoupling Agents / Q000494:pharmacology
chemical_list: D002614:Chelating Agents; D015853:Cysteine Proteinase Inhibitors; D004151:Dipeptides; D018722:Nicotinic Agonists; D014475:Uncoupling Agents; D010725:Phosphocreatine; D012402:Rotenone; C070379:1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester; C071482:calpeptin; D018698:Glutamic Acid; D004533:Egtazic Acid; D009538:Nicotine; D000105:Acetyl Coenzyme A; D010728:Phosphoenolpyruvate; D000255:Adenosine Triphosphate; D002154:Calpain; D002118:Calcium
keywords: Alzheimer's; Amyloid; Calcium; Calpain; Energy