PMID- 11750901
OWN - NLM
STAT- MEDLINE
DCOM- 20020305
LR  - 20220311
IS  - 0006-8993 (Print)
IS  - 0006-8993 (Linking)
VI  - 924
IP  - 2
DP  - 2002 Jan 11
TI  - Depletion of intracellular calcium stores is toxic to SH-SY5Y neuronal cells.
PG  - 159-66
AB  - Inhibiting Ca(2+) uptake by the sarcoendoplasmic reticular Ca(2+)-ATPase pump 
      (SERCA) causes release of Ca(2+) from the endoplasmic reticulum (ER), increased 
      cytosolic Ca(2+) ([Ca(2+)](cyt)) and depletion of ER Ca(2+) stores. These studies 
      were designed to test the effects of SERCA inhibition on neuronal viability, 
      using as a model the human neuroblastoma cell line, SH-SY5Y. Continuous exposure 
      to the SERCA inhibitor thapsigargin (TG) decreased SH-SY5Y viability to <30% 
      after 48 h exposure, and produced DNA laddering. Two other SERCA inhibitors, BHQ 
      and cyclopiazonic acid CPA, were similarly toxic, although at 1000-fold higher 
      concentrations. BHQ and CPA toxicity was prevented by removing drug within 
      several hours, whereas TG toxicity was essentially irreversible. All three SERCA 
      inhibitors caused an increase in [Ca(2+)](cyt) that was partially blocked by the 
      ryanodine receptor inhibitors, dantrolene and DHBP. Pretreatment with 40 microM 
      dantrolene gave substantial protection against TG- or BHQ-induced cell death but 
      it did not inhibit death from staurosporine, which does not cause release of ER 
      Ca(2+). DHBP (20-100 microM) also gave partial protection against TG toxicity, as 
      did ruthenium red (2 microM), but not ryanodine (10 microM). Inhibition of 
      capacitative Ca(2+) entry with EGTA or LaCl(3) or low extracellular Ca(2+), or 
      chelation of [Ca(2+)](cyt) with BAPTA-AM, failed to inhibit TG toxicity, although 
      they prevented increases in [Ca(2+)](cyt) caused by TG. Taken together, these 
      data suggest that toxicity caused by SERCA inhibition in SH-SY5Y cells is caused 
      by ER Ca(2+) depletion, which triggers an apparent apoptotic pathway.
FAU - Nguyen, Henry N
AU  - Nguyen HN
AD  - Department of Pharmacology, George Washington University Medical Center, 2300 I 
      St. NW, 20037, Washington, DC, USA
FAU - Wang, Chen
AU  - Wang C
FAU - Perry, David C
AU  - Perry DC
LA  - eng
GR  - NS34706/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - Netherlands
TA  - Brain Res
JT  - Brain research
JID - 0045503
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Hydroquinones)
RN  - 0 (Indoles)
RN  - 0 (Muscle Relaxants, Central)
RN  - 0 (Sesquiterpenes)
RN  - 139890-68-9 (1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid 
      acetoxymethyl ester)
RN  - 26XK13B61B (2,5-di-tert-butylhydroquinone)
RN  - 41929-10-6 (alatolide)
RN  - 526U7A2651 (Egtazic Acid)
RN  - 67526-95-8 (Thapsigargin)
RN  - EC 3.6.3.8 (Sarcoplasmic Reticulum Calcium-Transporting ATPases)
RN  - EC 7.2.2.10 (Calcium-Transporting ATPases)
RN  - F64QU97QCR (Dantrolene)
RN  - H88EPA0A3N (Staurosporine)
RN  - SY7Q814VUP (Calcium)
RN  - X9TLY4580Z (cyclopiazonic acid)
SB  - IM
MH  - Apoptosis/drug effects/*physiology
MH  - Brain Ischemia/metabolism
MH  - Calcium/*metabolism
MH  - Calcium-Transporting ATPases/antagonists & inhibitors
MH  - Cytosol/metabolism
MH  - Dantrolene/pharmacology
MH  - Egtazic Acid/*analogs & derivatives/pharmacology
MH  - Endoplasmic Reticulum/metabolism
MH  - Enzyme Inhibitors/pharmacology
MH  - Humans
MH  - Hydroquinones/pharmacology
MH  - Indoles/pharmacology
MH  - Muscle Relaxants, Central/pharmacology
MH  - *Neuroblastoma
MH  - Neurons/*cytology/*metabolism
MH  - Sarcoplasmic Reticulum Calcium-Transporting ATPases
MH  - Sesquiterpenes/pharmacology
MH  - Staurosporine/pharmacology
MH  - Thapsigargin/pharmacology
MH  - Tumor Cells, Cultured
EDAT- 2001/12/26 10:00
MHDA- 2002/03/07 10:01
CRDT- 2001/12/26 10:00
PHST- 2001/12/26 10:00 [pubmed]
PHST- 2002/03/07 10:01 [medline]
PHST- 2001/12/26 10:00 [entrez]
AID - S0006899301032292 [pii]
AID - 10.1016/s0006-8993(01)03229-2 [doi]
PST - ppublish
SO  - Brain Res. 2002 Jan 11;924(2):159-66. doi: 10.1016/s0006-8993(01)03229-2.