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Molecular mechanisms of subtype-specific inhibition of neuronal T-type calcium channels by ascorbate.

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.

SUBMITTER: Nelson MT

PROVIDER: S-EPMC6673317 | biostudies-literature | 2007 Nov

REPOSITORIES: biostudies-literature

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Molecular mechanisms of subtype-specific inhibition of neuronal T-type calcium channels by ascorbate.

Nelson Michael T MT Joksovic Pavle M PM Su Peihan P Kang Ho-Won HW Van Deusen Amy A Baumgart Joel P JP David Laurence S LS Snutch Terrance P TP Barrett Paula Q PQ Lee Jung-Ha JH Zorumski Charles F CF Perez-Reyes Edward E Todorovic Slobodan M SM

The Journal of neuroscience : the official journal of the Society for Neuroscience 20071101 46

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 ...[more]

PMID: 18003836

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Project description:Calcium ion channels coordinate an astounding number of cellular functions. Surprisingly, only 10 Ca(V)alpha(1) subunit genes encode the structural cores of all voltage-gated calcium channels. What mechanisms exist to modify the structure of calcium channels and optimize their coupling to the rich spectrum of cellular functions? Growing evidence points to the contribution of post-translational alternative processing of calcium channel RNA as the main mechanism for expanding the functional potential of this important gene family. Alternative splicing of RNA is essential during neuronal development where fine adjustments in protein signaling promote and inhibit cell-cell interactions and underlie axonal guidance. However, attributing a specific functional role to an individual splice isoform or splice site has been difficult. In this regard, studies of ion channels are advantageous because their function can be monitored with precision, allowing even subtle changes in channel activity to be detected. Such studies are especially insightful when coupled with information about isoform expression patterns and cellular localization. In this paper, we focus on two sites of alternative splicing in the N-type calcium channel Ca(V)2.2 gene. We first describe cassette exon 18a that encodes a 21 amino acid segment in the II-III intracellular loop region of Ca(V)2.2. Here, we show that e18a is upregulated in the nervous system during development. We discuss these new data in light of our previous reports showing that e18a protects the N-type channel from cumulative inactivation. Second, we discuss our published data on exons e37a and e37b, which encode 32 amino acids in the intracellular C-terminus of Ca(V)2.2. These exons are expressed in a mutually exclusive manner. Exon e37a-containing Ca(V)2.2 mRNAs and their resultant channels express at higher density in dorsal root ganglia and, as we showed recently, e37a increases N-type channel sensitivity to G-protein-mediated inhibition, as compared to generic e37b-containing N-type channels.

Dataset Information

Molecular mechanisms of subtype-specific inhibition of neuronal T-type calcium channels by ascorbate.

Publications

Molecular mechanisms of subtype-specific inhibition of neuronal T-type calcium channels by ascorbate.

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