Molecular mechanisms of subtype-specific inhibition of neuronal T-type calcium channels by ascorbate.
J Neurosci
; 27(46): 12577-83, 2007 Nov 14.
Article
em En
| MEDLINE
| ID: mdl-18003836
ABSTRACT
T-type Ca2+ channels (T-channels) are involved in the control of neuronal excitability and their gating can be modulated by a variety of redox agents. Ascorbate is an endogenous redox agent that can function as both an anti- and pro-oxidant. Here, we show that ascorbate selectively inhibits native Ca(v)3.2 T-channels in peripheral and central neurons, as well as recombinant Ca(v)3.2 channels heterologously expressed in human embryonic kidney 293 cells, by initiating the metal-catalyzed oxidation of a specific, metal-binding histidine residue in domain 1 of the channel. Our biophysical experiments indicate that ascorbate reduces the availability of Ca(v)3.2 channels over a wide range of membrane potentials, and inhibits Ca(v)3.2-dependent low-threshold-Ca2+ spikes as well as burst-firing in reticular thalamic neurons at physiologically relevant concentrations. This study represents the first mechanistic demonstration of ion channel modulation by ascorbate, and suggests that ascorbate may function as an endogenous modulator of neuronal excitability.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Ácido Ascórbico
/
Bloqueadores dos Canais de Cálcio
/
Ativação do Canal Iônico
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Canais de Cálcio Tipo T
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Neurônios
Limite:
Animals
/
Humans
Idioma:
En
Ano de publicação:
2007
Tipo de documento:
Article