New factors contributing to dynamic calcium regulation in the skeletal muscle triad—a crowded place

Abstract

Skeletal muscle is a highly organized tissue that has to be optimized for fast signalling events conveying electrical excitation to contractile response. The site of electro-chemico-mechanical coupling is the skeletal muscle triad where two membrane systems, the extracellular ttubules and the intracellular sarcoplasmic reticulum, come into very close contact. Structure fits function here and the signalling proteins DHPR and RyR1 were the first to be discovered to bridge this gap in a conformational coupling arrangement. Since then, however, new proteins and more signalling cascades have been identified just in the last decade, adding more diversity and fine tuning to the regulation of excitation-contraction coupling (ECC) and control over Ca 2+ store content. The concept of Ca 2+ entry into working skeletal muscle has become attractive again with the experimental evidence summarized in this review. Store-operated Ca 2+ entry (SOCE), excitation-coupled Ca 2+ entry (ECCE), action-potential-activated Ca 2+ current (APACC), and retrograde EC-coupling (ECC) are new concepts additional to the conventional orthograde ECC; they have provided fascinating new insights into muscle physiology. In this review, we discuss the discovery of these pathways, their potential roles, and the signalling proteins involved that show that the triad may become a crowded place in time.

CaV1.1: The atypical prototypical voltage-gated Ca2+ channel

“…Even though the molecular identity of the permeation pathway remains a matter of some debate [3,4], the voltage-sensor for activation of ECCE is by definition housed in Ca V 1.1. For this reason, any physiological impact of ECCE is directly controlled by Ca V 1.1.…”

“…Moreover, Ca V 1.1 requires the influence of the type 1 ryanodine receptor (RyR1) to support its L-type channel function. However, the physiological significance of L-type Ca 2+ current via Ca V 1.1 is uncertain [3,4], and the ability of Ca V 1.1 to carry out its most important function does not depend on Ca 2+ flux at all [5,6]. …”

Excitation-contraction coupling in mammalian skeletal muscle: Blending old and last-decade research

“…That entry was a small rectifying highly Ca 2+ selective current, not affected by Ca 2+ channel blockers (Hoth and Penner, 1992) called Ca 2+ Release Activated Ca 2+ Current (I CRAC ). Two research groups then identified in 2005 the Stromal Interacting Molecule (STIM) as a single-pass transmembrane EF-hand protein that acts as Ca 2+ sensor in the endoplasmic reticulum lumen of many cells with a low affinity of ~200-600 μM (Liou et al, 2005;Roos et al, 2005;Zhang et al, 2005;Stathopulos et al, 2006;Canato et al, 2010;Friedrich et al, 2010). In 2006 it was confirmed the interaction of STIM with a protein in the plasma membrane called Orai, which constitutes the transmembrane pore of the CRAC complex (Vig et al, 2006b(Vig et al, , 2006aFeske et al, 2006;Prakriya et al, 2006;Soboloff et al, 2006;Hou et al, 2018).…”

Proteomic profiling of impaired excitation–contraction coupling and abnormal calcium handling in muscular dystrophy

“…Most importantly the α1S‐subunit serves as voltage sensor in excitation–contraction coupling [ 50 , 51 , 52 ], but also functions as an L‐type Ca 2+ ‐channel which allows ECCE [ 62 ]. Of note, multiple signalling interactions occur in a bidirectional way at the triad junction between the transverse tubular L‐type Ca 2+ ‐channel and the Ca 2+ ‐release channel of the sarcoplasmic reticulum [ 63 ]. On the one hand, depolarisation‐induced conformational changes in the voltage‐sensing L‐type Ca 2+ ‐channel translate into opening of the Ca 2+ ‐release channel in the sarcoplasmic reticulum during orthograde signalling that regulates excitation–contraction coupling [ 64 ].…”