PMID- 14511120
OWN - NLM
STAT- MEDLINE
DCOM- 20031106
LR  - 20220316
IS  - 0022-3042 (Print)
IS  - 0022-3042 (Linking)
VI  - 87
IP  - 2
DP  - 2003 Oct
TI  - Alteration in calcium channel properties is responsible for the neurotoxic action 
      of a familial frontotemporal dementia tau mutation.
PG  - 427-36
AB  - Tau, a microtubule binding protein, is not only a major component of 
      neurofibrillary tangles in Alzheimer's disease, but also a causative gene for 
      hereditary frontotemporal dementia and parkinsonism linked to chromosome 17 
      (FTDP-17). We show here that an FTDP-17 tau mutation (V337M) in SH-SY5Y cells 
      reduces microtubule polymerization, increases voltage-dependent calcium current 
      (ICa) density, and decreases ICa rundown. The reduced rundown of ICa by V337M was 
      significantly inhibited by nifedipine (L-type Ca channel blocker), whereas 
      omega-conotoxin GVIA (N-type Ca channel blocker) showed smaller effects, 
      indicating that tau mutations affect L-type calcium channel activity. The 
      depolarization-induced increase in intracellular calcium was also significantly 
      augmented by the V337M tau mutation. Treatment with a microtubule polymerizing 
      agent (taxol), an adenylyl cyclase inhibitor, or a protein kinase A (PKA) 
      inhibitor, counteracted the effects of mutant tau on ICa. Taxol also attenuated 
      the Ca2+ response to depolarization in cells expressing mutant tau. Apoptosis in 
      SH-SY5Y cells induced by serum deprivation was exacerbated by the V337M mutation, 
      and nifedipine, taxol, and a PKA inhibitor significantly protected cells against 
      apoptosis. Our results indicate that a tau mutation which decreases its 
      microtubule-binding ability augments calcium influx by depolymerizing 
      microtubules and activating adenylyl cyclase and PKA.
FAU - Furukawa, Katsutoshi
AU  - Furukawa K
AD  - Laboratory of Neurosciences, Gerontology Research Center, National Institute on 
      Aging, National Institutes of Health, Baltimore, Maryland 21224, USA. 
      furukawaka@grc.nia.nih.gov
FAU - Wang, Yue
AU  - Wang Y
FAU - Yao, Pamela J
AU  - Yao PJ
FAU - Fu, Weiming
AU  - Fu W
FAU - Mattson, Mark P
AU  - Mattson MP
FAU - Itoyama, Yasuto
AU  - Itoyama Y
FAU - Onodera, Hiroshi
AU  - Onodera H
FAU - D'Souza, Ian
AU  - D'Souza I
FAU - Poorkaj, Parvone H
AU  - Poorkaj PH
FAU - Bird, Thomas D
AU  - Bird TD
FAU - Schellenberg, Gerard D
AU  - Schellenberg GD
LA  - eng
PT  - Journal Article
PL  - England
TA  - J Neurochem
JT  - Journal of neurochemistry
JID - 2985190R
RN  - 0 (Calcium Channels)
RN  - 0 (Calcium Channels, L-Type)
RN  - 0 (tau Proteins)
RN  - E0399OZS9N (Cyclic AMP)
RN  - SY7Q814VUP (Calcium)
SB  - IM
MH  - Calcium/metabolism
MH  - Calcium Channels/drug effects/*metabolism
MH  - Calcium Channels, L-Type/drug effects/genetics/metabolism
MH  - Cell Death/drug effects
MH  - Cell Line
MH  - Cyclic AMP/metabolism
MH  - Dementia/complications/*genetics
MH  - Humans
MH  - Membrane Potentials/physiology
MH  - Microtubules/metabolism
MH  - Mutation
MH  - Neuroblastoma/drug therapy/metabolism
MH  - Neurons/cytology/drug effects/metabolism
MH  - Parkinsonian Disorders/complications/*genetics
MH  - Patch-Clamp Techniques
MH  - tau Proteins/*genetics/toxicity
EDAT- 2003/09/27 05:00
MHDA- 2003/11/07 05:00
CRDT- 2003/09/27 05:00
PHST- 2003/09/27 05:00 [pubmed]
PHST- 2003/11/07 05:00 [medline]
PHST- 2003/09/27 05:00 [entrez]
AID - 2020 [pii]
AID - 10.1046/j.1471-4159.2003.02020.x [doi]
PST - ppublish
SO  - J Neurochem. 2003 Oct;87(2):427-36. doi: 10.1046/j.1471-4159.2003.02020.x.