The effect of α2‐δ and other accessory subunits on expression and properties of the calcium channel α1G

Abstract

Voltage-dependent calcium channels and currents in native neurons and other cells have been divided into high voltage activated (HVA) and low voltage activated (LVA) (Carbone & Lux, 1984;Nowycky et al. 1985). LVA currents can be distinguished by their activation at smaller depolarizations, near to the resting potential, and by their rapid inactivation (Huguenard, 1996). At the single channel level, channels with a small unitary conductance activate over the same voltage range (Carbone & Lux, 1984). Native T-type channels are heterogeneous (Kobrinsky et al. 1994;Huguenard, 1996), suggesting that they comprise more than one subtype of channel. A new subfamily of voltage-dependent calcium channel á1 subunit genes (comprising á1G, á1H and á1I) has recently been cloned, whose structure is superficially similar to the previously cloned HVA á1 subunits A, B, C, D, E and S (Perez-Reyes et al. 1998;Lee et al. 1999), having four domains, each with a voltage sensor and a pore-forming P loop. However, there are a number of regions where the homology is very low, particularly in the intracellular linkers and the N and C termini. These novel channels, when expressed, form rapidly inactivating LVA currents that also have a small single channel conductance and slowly deactivating tail currents like native T-type currents (Carbone & Lux, 1984;Armstrong & Matteson, 1985). Recently, using an antisense approach, evidence has been obtained that T-type currents in primary sensory neurons are generated by the á1G, H and I family (Lambert et al. 1998). The HVA channels are all thought to form heteromeric channels with the accessory subunits á2-ä, â and possibly ã. The accessory subunits, particularly â subunits, have marked effects on the assembly of functional channels at the plasma membrane. In expression systems, the â subunits increase the number of plasma membrane channels (Chien et al. 1995;Shistik et al. 1995;Brice et al. 1997) and also affect the voltage dependence and kinetics of activation and inactivation (Jones et al. 1998). Inactivation kinetics are

Molecular Physiology of Low-Voltage-Activated T-type Calcium Channels

“…Similarly, coexpression of cloned ␤-subunits has little or no effect on cloned T-type channel activity (100). In contrast, coexpression with either ␣ 2 ␦ 1 or ␣ 2 ␦ 2 was found to double the size of Ca v 3.1-mediated currents (100,132). Concomitant immunolocalization studies supported the contention that this rise in currents was due to increased expression of ␣ 1 -␣ 2 ␦ 1 complexes at the plasma membrane (100).…”

“…Antisense depletion of ␤-subunits causes profound reductions in HVA channel density; however, this treatment has no effect on T-type channels recorded from the same neurons (226,234). Similarly, coexpression of cloned ␤-subunits has little or no effect on cloned T-type channel activity (100). In contrast, coexpression with either ␣ 2 ␦ 1 or ␣ 2 ␦ 2 was found to double the size of Ca v 3.1-mediated currents (100,132).…”

Elevated Thalamic Low-Voltage-Activated Currents Precede the Onset of Absence Epilepsy in the SNAP25-Deficient Mouse MutantColoboma

“…It is also supported by the lack of biochemical evidence for direct interactions between wild-type ␣1G and other poreforming or regulatory Ca 2ϩ channel subunits, except for the finding that functional expression of ␣1G increases with coexpression of ␣2␦ and ␤1b subunits (Dolphin et al, 1999). These data demonstrate that mutations of Ca 2ϩ channel subunit genes are not required to induce the elevated LVA Ca 2ϩ currents in thalamic neurons that are associated with SWDs.…”

The Ducky Mutation in Cacna2d2 Results in Altered Purkinje Cell Morphology and Is Associated with the Expression of a Truncated α2δ-2 Protein with Abnormal Function

“…Previous in vitro studies have shown that ␣2␦-1, ␣2␦-2, and ␣2␦-3 subunits act to increase the maximum conductance of a number of expressed calcium channel ␣ 1 /␤ subunit combinations at the whole cell level (2,(43)(44)(45)(46). However, this may be dependent to some extent on the specific combination of ␣ 1 and ␤ subunits expressed.…”