title: Paradoxical effects of sarco/endoplasmic reticulum Ca(2+)-ATPase (SERCA) activator gingerol on NG115-401L neuronal cells: failure to augment ER Ca(2+) uptake and protect against ER stress-induced cell death.
abstract: Perturbation of endoplasmic reticulum (ER) Ca(2+) homeostasis and ER stress are thought to underlie a spectrum of defects encompassing major societal diseases such as diabetes and neurodegeneration. In this report we used the NG115-401L neuronal cell line to test the hypothesis that neuroprotection against ER stress may be conferred by pharmacological stimulation of the sarco/endoplasmic reticulum Ca(2+)-ATPase (SERCA) pumps. We report that the SERCA activator gingerol stimulates SR microsomal Ca(2+)-ATPase activity and restores enzymatic function in the presence of potent SERCA blockers. Yet, enzyme protection in isolated membranes does not extend to protection from ER stress in intact NG115-401L cells. Surprisingly, gingerol not only failed to protect cells from SERCA blocker-induced ER stress and cell death, the compound itself potently induced cell death. Also, we report that gingerol failed to augment ER Ca(2+) uptake, a result contradictory to what has been observed in muscle. Unexpectedly, gingerol discharged ER Ca(2+) stores and coupled robustly to Ca(2+) influx pathways. These observations suggest that gingerol is not acting as a traditional SERCA blocker as thapsigargin mediated ER Ca(2+) store depletion fails to stimulate Ca(2+) influx in the NG115-401L cell phenotype. Moreover, cell death induced by gingerol, in contrast to the classic SERCA inhibitors, is not accompanied by increases in reactive oxygen species production or enzymatic caspase activity. These results argue for a finer regulatory control on SERCA function with gingerol's actions revealing potentially novel routes of coupling altered pump regulation to the assembly of functional Ca(2+) influx units and activation of cell death pathways.
authors.affiliation: Department of Physiology & Pharmacology, Thomas J. Long School of Pharmacy and Health Sciences, University of the Pacific, 3601 Pacific Avenue, Stockton, CA 95211, United States.
authors.forename: Changfeng
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Pharmaceutical and Administrative Sciences, College of Pharmacy, Western New England University, 1215 Wilbraham Road, Springfield, MA 01119, United States.
authors.forename: Diptiman D
authors.initials: DD
authors.lastname: Bose
authors.affiliation: Department of Physiology & Pharmacology, Thomas J. Long School of Pharmacy and Health Sciences, University of the Pacific, 3601 Pacific Avenue, Stockton, CA 95211, United States. Electronic address: dthomas1@pacific.edu.
authors.forename: David W
authors.initials: DW
authors.lastname: Thomas
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002118:Calcium / Q000378:metabolism*; D002396:Catechols / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D020536:Enzyme Activators / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005233:Fatty Alcohols / Q000494:pharmacology*; D006706:Homeostasis / Q000187:drug effects; D007211:Indoles / Q000494:pharmacology; D008861:Microsomes / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D011817:Rabbits; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019284:Thapsigargin / Q000494:pharmacology
chemical_list: D002396:Catechols; D020536:Enzyme Activators; D004791:Enzyme Inhibitors; D005233:Fatty Alcohols; D007211:Indoles; D019284:Thapsigargin; C007845:gingerol; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D002118:Calcium; C000543:cyclopiazonic acid
keywords: Calcium; ER stress; Gingerol; Neuroprotection; SERCA