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Siegel GJ, Agranoff BW, Albers RW, et al., editors. Basic Neurochemistry: Molecular, Cellular and Medical Aspects. 6th edition. Philadelphia: Lippincott-Raven; 1999.

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Basic Neurochemistry: Molecular, Cellular and Medical Aspects. 6th edition.

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Box 23-1Voltage-Gated Calcium Ion Channels

Voltage-gated Ca2+ channels are heterogeneous in structure and regulation. Multiple types of voltage-dependent Ca2+ channels have been characterized physiologically [1] and multiple Ca2+-channel subunits have been cloned [2]. Differential regional expression of specific subunit isoforms and cellular localization of Ca2+-channel types are well documented. These differences and the existence of multiple types of Ca2+ channels in individual neurons have been postulated to be important in controlling many Ca2+-dependent cellular processes including neurotransmitter release, gene expression and neurite outgrowth.

Ca2+ channels have been classified pharmacologically and biophysically. The channels are designated L-, T-, N-, P-, Q- and R-type. Each channel has different voltage ranges and rates for activation and inactivation [3]. Low-voltage-activated (LVA) T-type currents are distinguished from high-voltage-activated (HVA) L-, N-, P-, Q- and R-type currents based on the relatively hyperpolarized potential at which they are activated. T-type channels, believed to function as a pacemaker, typically are activated slowly and inactivated rapidly, whereas the HVA channels are activated much more rapidly and vary in the extent and rate of their inactivation. The N-type typically are inactivated more rapidly then the L-, P- and Q-types. The HVA channels can be distinguished by their pharmacological sensitivities to specific blockers and toxins [4]. The L-type channels are found in skeletal as well as neuronal tissue and are sensitive to dihydropyridines such as the agonist BayK-2844 and the antagonist nifedipine [5]. The N-type channels are irreversibly blocked by the snail toxin ω-conotoxin GVIA and are thought to be responsible for neurotransmitter release at synaptic junctions. Another snail toxin, ω-conotoxin MVIIC, inhibits N-, P- and Q-type currents. Preferential block by the spider toxin ω-agatoxin-IVA can be used to isolate the P-type channels, which were initially identified in Purkinje cells due to the high level of expression in those cells. Insensitivity to all these compounds defines the R-type channel that may actually be comprised of multiple channel types. The T-type channels and the recombinant “R-type” currents have a higher sensitivity to blockade by Ni2+.

Each channel type has been cloned and is composed of a large α1 subunit in combination with one or more smaller accessory subunits [6]. At least six α1, four β, one α2 and one δ subunits have been cloned [2]. The large α1 subunit has four domains, each with six transmembrane segments, which form the ion pore of the channel. Five neuronal α1 subunits (denoted A-E) have been described to date. Heterologous expression of the α1 subunits in recombinant systems has pharmacological properties similar to those of native Ca2+ channel types (L-type: α1C, α1D; N-type: α1B; Q/P-type: α1A; R-type: α1E). The pairing of molecular clones with functional channel types is, however, incomplete and may be affected by the coordinate expression of one or more auxiliary subunits. The subunit composition of native Ca2+ channels is further complicated by the diversity of the auxiliary subunits α2(A-E)/δ, β1–4 and γ described to date. The functional roles of all these subunits are not fully understood.

—Torben R. Neelands and Robert L. Macdonald

References

1.
Tsien R W, Lipscombe D, Madison D V, Bley R K, Fox A P. Multiple types of neuronal calcium channels and their selective modulation. Trends Neurosci. 1988;11:431–438. [PubMed: 2469160]
2.
Perez-Reyes E, Schneider T. Molecular biology of calcium channels. Kidney Int. 1995;48:1111–1124. [PubMed: 8569073]
3.
Catterall W A. Molecular properties of sodium and calcium channels. J. Bioenerg. Biomembr. 1996;28:219–230. [PubMed: 8807398]
4.
Adams M E, Olivera B M. Neurotoxins: Overview of an emerging research technology. Trends Neurosci. 1994;17:151–155. [PubMed: 7517594]
5.
Hockerman G H, Peterson B Z, Johnson B D, Catterall W A. Molecular determinants of drug binding and action on L-type calcium channels. Annu. Rev. Pharmacol. Toxicol. 1997;37:361–396. [PubMed: 9131258]
6.
De Waard M, Gurnett C A, Campbell K P. Structural and functional diversity of voltage-activated calcium channels. Ion Channels. 1996;4:41–87. [PubMed: 8744206]

From: Ca2+ Signaling

Copyright © 1999, American Society for Neurochemistry.

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