Ca(V)1.1: The atypical prototypical voltage-gated Ca²⁺ channel

Abstract

Ca(V)1.1 is the prototype for the other nine known Ca(V) channel isoforms, yet it has functional properties that make it truly atypical of this group. Specifically, Ca(V)1.1 is expressed solely in skeletal muscle where it serves multiple purposes; it is the voltage sensor for excitation-contraction coupling and it is an L-type Ca²⁺ channel which contributes to a form of activity-dependent Ca²⁺ entry that has been termed Excitation-coupled Ca²⁺ entry. The ability of Ca(V)1.1 to serve as voltage-sensor for excitation-contraction coupling appears to be unique among Ca(V) channels, whereas the physiological role of its more conventional function as a Ca²⁺ channel has been a matter of uncertainty for nearly 50 years. In this chapter, we discuss how Ca(V)1.1 supports excitation-contraction coupling, the possible relevance of Ca²⁺ entry through Ca(V)1.1 and how alterations of Ca(V)1.1 function can have pathophysiological consequences. This article is part of a Special Issue entitled: Calcium channels.

Fig. 1. Schematic representation of the Ca_V1.1

Cartoon illustrating the membrane topology of Ca_V1.1. Like Na_V channels and the other nine members of the Ca_V family, Ca_V1.1 is a single polypeptide composed of four relatively conserved repeats (I, II, II and IV) containing six α-helices apiece. The fourth α-helix of each has a regularly spaced sequence of basic residues that is believed to be critical for voltage-sensing. The segments linking the repeats, as well as the amino- and carboxyl-termini, are intracellular. The I-II-linker is the site of interaction with the predominantly intracellular β_1a subunit (illustrated). The red box in the II-III loop represents the “critical domain” which is essential for engaging EC coupling (residues 720-765) [59]. The black box within the blue box represents the “A domain” (residues 681-690) [66,68]. The green box represents the highly conserved carboxyl-terminal domain [65]. The carboxyl terminus contains a proteolytic cleavage site at residue A1664 (hatch) [167], although this cleavage does not appear to affect the ability of Ca_V1.1 to couple to RyR1 [168]. The yellow segment indicates the position of an alternative splice (exon29) in the extracellular S3-S4 linker of Repeat IV [158]. The red explosions indicate known hypokalemic periodic paralysis (R528H, R900H and R1239H; please see text for references) mutations and the yellow stars signify residue substitutions that have been linked to malignant hyperthermia susceptibility (R174W, R1086H/C/S and T1354S; please see text for references).

Fig. 2. Tetradic organization of Ca_V1.1 channels at plasma membrane junctions requires the Ca_Vβ_1a subunit

Electron micrographs of freeze-fracture replicas of zebrafish membrane junctions are shown in both panels. In wild-type muscle (left), Ca_V1.1-containing channels exist in tetrads aligned with the four subunits of every other RyR1 homotetramer; each tetrad is highlighted by a red dot. In relaxed, or β₁ null, muscle, the Ca_V1.1 particles are sparse and tetrads are absent (right). Figure modified from Schredelseker et al. [30] with permission from the publisher; ©The Proceedings of the National Academy of Sciences of the USA, 2005.

Fig. 3. Restoration of L-type current and EC coupling in dysgenic (Ca_V1.1 null) myotubes

EC coupling, as indicated by contractions elicited by focal electrical (top row), and Ca²⁺ currents recorded at +30 mV in the whole-cell configuration (bottom row) from normal myotubes (left panels), naïve dysgenic myotubes (middle panels) and Ca_V1.1-expressing dysgenic myotubes (right panels). Note the persistence of some T-type Ca²⁺ current in naïve dysgenic myotubes. Figure modified from Tanabe et al. [49] with permission from the publisher.

Fig. 4. Communication between Ca_V1.1 and RyR1 is bi-directional

The orthograde, or EC coupling, signal is communicated from Ca_V1.1 to RyR1. This signal is absent from dyspedic (RyR1 null) myotubes (bottom left). This signal is restored by reintroduction of the SR Ca²⁺ release channel (bottom right). Interestingly, dyspedic myotubes have meagre L-type Ca²⁺ current (top left), despite normal Ca_V1.1 expression. Reintroduction of RyR1 substantially increases L-type current density (top right), indicating that conformational coupling between Ca_V1.1 and RyR1 also produces a “retrograde” signal that serves to increase Ca_V1.1 relative P_o. Figure modified from Nakai et al. [88] and Grabner et al. [92] with permission from the publishers.

Fig. 5. A high-conductance Ca_V1.1 splice variant expressed in developing skeletal muscle

L-type currents recorded from dysgenic myotubes expressing either an adult α_1S isoform (Ca_V1.1a) [1] or an embryonic α_1S isoform lacking exon 29 [158] are shown in (A-left). A comparison of I-V relationships shows that Ca_V1.1e has considerably larger current density and a hyperpolarizing shift in the voltage-dependence of activation relative to Ca_V1.1a (A-right). Myoplasmic Ca²⁺ transients are augmented for Ca_V1.1e (B-left), but the increase and hyperpolarizing shift in Fluo-4 signal represents the contribution of the L-type current because the ΔF/F-V relationship is nearly identical when Ca²⁺ entry via Ca_V1.1 is blocked by Cd²⁺ and La³⁺ (B-right). Figure modified from Tuluc et al. [158] with permission of the publishers; © Elsevier, 2009.