PMID- 20132834
OWN - NLM
STAT- MEDLINE
DCOM- 20100409
LR  - 20220318
IS  - 1096-0333 (Electronic)
IS  - 0041-008X (Linking)
VI  - 244
IP  - 3
DP  - 2010 May 1
TI  - The effects of 3,4-methylenedioxymethamphetamine (MDMA) on nicotinic receptors: 
      intracellular calcium increase, calpain/caspase 3 activation, and functional 
      upregulation.
PG  - 344-53
LID - 10.1016/j.taap.2010.01.014 [doi]
AB  - Previous work by our group demonstrated that homomeric alpha7 nicotinic 
      acetylcholine receptors (nAChR) play a role in the neurotoxicity induced by 
      3,4-methylenedioxymethamphetamine (MDMA), as well as the binding affinity of this 
      drug to these receptors. Here we studied the effect of MDMA on the activation of 
      nAChR subtypes, the consequent calcium mobilization, and calpain/caspase 3 
      activation because prolonged Ca(2+) increase could contribute to cytotoxicity. As 
      techniques, we used fluorimetry in Fluo-4-loaded PC12 cells and electrophysiology 
      in Xenopus oocytes. MDMA produced a rapid and sustained increase in calcium 
      without reaching the maximum effect induced by ACh. It also 
      concentration-dependently inhibited the response induced by ACh, nicotine, and 
      the specific alpha7 agonist PNU 282987 with IC(50) values in the low micromolar 
      range. Similarly, MDMA induced inward currents in Xenopus oocytes transfected 
      with human alpha7 but not with alpha4beta2 nAChR and inhibited ACh-induced 
      currents in both receptors in a concentration-dependent manner. The calcium 
      response was inhibited by methyllycaconitine (MLA) and alpha-bungarotoxin but not 
      by dihydro-beta-erythroidine. These results therefore indicate that MDMA acts as 
      a partial agonist on alpha7 nAChRs and as an antagonist on the heteromeric 
      subtypes. Subsequently, calcium-induced Ca(2+) release from the endoplasmic 
      reticulum and entry through voltage-operated calcium channels are also implicated 
      as proved using specific antagonists. In addition, treatment with MDMA for 24 h 
      significantly increased basal Ca(2+) levels and induced an increase in 
      alpha-spectrin breakdown products, which indicates that calpain and caspase 3 
      were activated. These effects were inhibited by pretreatment with MLA. Moreover, 
      pretreatment with MDMA induced functional upregulation of calcium responses to 
      specific agonists of both heteromeric and alpha7 nAChR. Sustained calcium entry 
      and calpain activation could favor the activation of Ca(2+)-dependent enzymes 
      such as protein kinase C and nitric oxide synthase, which are involved in the 
      generation of ROS and the blockade of the dopamine transporter. This, together 
      with caspase 3 activation, must play a role in MDMA-induced cytotoxicity.
CI  - Copyright 2010 Elsevier Inc. All rights reserved.
FAU - Garcia-Rates, Sara
AU  - Garcia-Rates S
AD  - Unitat de Farmacologia i Farmacognosia, Facultat de Farmacia, Nucli Universitari 
      de Pedralbes, Universitat de Barcelona, Institut de Biomedicina de la UB (IBUB), 
      Av. Joan XXIII s/n, 08028 Barcelona, Spain.
FAU - Camarasa, Jordi
AU  - Camarasa J
FAU - Sanchez-Garcia, Ana I
AU  - Sanchez-Garcia AI
FAU - Gandia, Luis
AU  - Gandia L
FAU - Escubedo, Elena
AU  - Escubedo E
FAU - Pubill, David
AU  - Pubill D
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20100202
PL  - United States
TA  - Toxicol Appl Pharmacol
JT  - Toxicology and applied pharmacology
JID - 0416575
RN  - 0 (Calcium Channels)
RN  - 0 (Nicotinic Agonists)
RN  - 0 (Receptors, Nicotinic)
RN  - 12634-43-4 (Spectrin)
RN  - 6M3C89ZY6R (Nicotine)
RN  - EC 3.4.22.- (Calpain)
RN  - EC 3.4.22.- (Caspase 3)
RN  - KE1SEN21RM (N-Methyl-3,4-methylenedioxyamphetamine)
RN  - N9YNS0M02X (Acetylcholine)
RN  - SY7Q814VUP (Calcium)
SB  - IM
CIN - Toxicol Appl Pharmacol. 2010 Dec 15;249(3):247-8; author reply 249-50. PMID: 
      20869982
MH  - Acetylcholine/metabolism
MH  - Animals
MH  - Calcium/*metabolism
MH  - Calcium Channels/drug effects/metabolism
MH  - Calpain/*metabolism
MH  - Caspase 3/*metabolism
MH  - Enzyme Activation
MH  - Humans
MH  - N-Methyl-3,4-methylenedioxyamphetamine/*toxicity
MH  - Nicotine/metabolism
MH  - Nicotinic Agonists/metabolism
MH  - Oocytes/drug effects/metabolism
MH  - PC12 Cells
MH  - Rats
MH  - Receptors, Nicotinic/*drug effects/metabolism
MH  - Spectrin/metabolism
MH  - Up-Regulation/drug effects
MH  - Xenopus/metabolism
EDAT- 2010/02/06 06:00
MHDA- 2010/04/10 06:00
CRDT- 2010/02/06 06:00
PHST- 2009/11/26 00:00 [received]
PHST- 2010/01/25 00:00 [revised]
PHST- 2010/01/26 00:00 [accepted]
PHST- 2010/02/06 06:00 [entrez]
PHST- 2010/02/06 06:00 [pubmed]
PHST- 2010/04/10 06:00 [medline]
AID - S0041-008X(10)00039-6 [pii]
AID - 10.1016/j.taap.2010.01.014 [doi]
PST - ppublish
SO  - Toxicol Appl Pharmacol. 2010 May 1;244(3):344-53. doi: 
      10.1016/j.taap.2010.01.014. Epub 2010 Feb 2.