Ion channels are ubiquitous membrane proteins that play fundamental roles in cell physiology such as muscle contraction, secretion, excitability and gene expression, among others. Ion channels that are permeant to Ca2+ are especially relevant to cells where this cation acts as a second messenger. In skeletal muscle, the Cav1.1 channel, a key element in excitation–contraction coupling, is composed of four subunits, α1, β, α2δ and γ (Arikkath & Campbell, 2003). The γ subunit was initially described as a major component of the muscle channel complex (Curtis & Catterall, 1984) and while heart muscle and other excitable cells express their α1, β and α2δ subunit counterparts, the γ subunit appeared for many years to be uniquely expressed in skeletal muscle (Jay et al. 1990) and its role on channel function remained largely unknown. This view changed dramatically when it was found that the stargazer mouse, a mutant mouse with epileptic seizures, is deficient in stargazin, a brain protein that is similar to the muscle γ subunit and whose absence leads to alterations in neuronal Ca2+ channel function. When stargazin is expressed in model systems, Ca2+ channel inactivation is accentuated and channel availability is significantly reduced (Letts et al. 1998). In skeletal muscle, inactivation of Cav1.1 channels is shifted to more positive potentials when the γ subunit is absent (Freise et al. 2000). In both cases, the role of the skeletal muscle γ1 subunit and the role of the neuronal γ2 subunit are to avoid an inappropriate Ca2+ entry. To these two family members of γ subunits, other members, γ3, γ4 and γ5, were added using conserved structural criteria (Burgess et al. 1999) and more recently, a cluster of three new γ genes (γ6, γ7 and γ8) was described and it was found that the profile of gene expression of these eight γ subunits is wider than previously thought (Burgess et al. 2001). Soon, new roles for members of the γ family emerged such as trafficking of ligand-gated ion channels to postsynaptic sites (Chu et al. 2001). More recently, a role of γ6 subunit as a potential regulator of the low-threshold cardiac Ca2+ channel Cav3.1 was characterized. It was found that γ6 has the unique ability to decrease current density by more than half without changing the voltage dependence of channel inactivation or the amount of total Cav3.1 protein (Hansen et al. 2004). It is unclear what makes γ6 so unique in the sense that it is the only γ subunit known to modulate the low-voltage-activated Ca2+ channel in atria, as is whether or not this subunit actually forms a physical association with the Cav3.1 channel. If it does, what is the nature of this interaction? In this issue of The Journal of Physiology, Lin et al. (2008) identify a domain in γ6 that is responsible for the inhibition of Cav3.1 currents. Furthermore, they describe a unique GxxxA motif within this domain that is required for the function of the γ6 subunit, pointing to helix–helix interactions and demonstrate physical interactions of this subunit with the channels. The γ6 subunit is highly selective on its inhibitory action, with no effects on the high-voltage-activated Ca2+ channel that is also expressed in heart muscle. This implies a fine modulation of Ca2+ entry in atria. Is this also the case in other tissues? Are there other unsuspected functions for the γ6 subunit? For example, the expression of low-voltage-activated Ca2+ channels in adult skeletal muscle is practically non-existent; it is the high-voltage-activated Cav1.1 channel that is the predominant one, and yet γ6 is expressed in this tissue.
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Aug 28, 2020
Huan Chen + 5
