Abstract
In the last decades the term Store-operated Ca2+ entry (SOCE) has been used in the scientific literature to describe an ubiquitous cellular mechanism that allows recovery of calcium (Ca2+) from the extracellular space. SOCE is triggered by a reduction of Ca2+ content (i.e. depletion) in intracellular stores, i.e. endoplasmic or sarcoplasmic reticulum (ER and SR). In skeletal muscle the mechanism is primarily mediated by a physical interaction between stromal interaction molecule-1 (STIM1), a Ca2+ sensor located in the SR membrane, and ORAI1, a Ca2+-permeable channel of external membranes, located in transverse tubules (TTs), the invaginations of the plasma membrane (PM) deputed to propagation of action potentials. It is generally accepted that in skeletal muscle SOCE is important to limit muscle fatigue during repetitive stimulation. We recently discovered that exercise promotes the assembly of new intracellular junctions that contains colocalized STIM1 and ORAI1, and that the presence of these new junctions increases Ca2+ entry via ORAI1, while improving fatigue resistance during repetitive stimulation. Based on these findings we named these new junctions Ca2+ Entry Units (CEUs). CEUs are dynamic organelles that assemble during muscle activity and disassemble during recovery thanks to the plasticity of the SR (containing STIM1) and the elongation/retraction of TTs (bearing ORAI1). Interestingly, similar structures described as SR stacks were previously reported in different mouse models carrying mutations in proteins involved in Ca2+ handling (calsequestrin-null mice; triadin and junctin null mice, etc.) or associated to microtubules (MAP6 knockout mice). Mutations in Stim1 and Orai1 (and calsequestrin-1) genes have been associated to tubular aggregate myopathy (TAM), a muscular disease characterized by: (a) muscle pain, cramping, or weakness that begins in childhood and worsens over time, and (b) the presence of large accumulations of ordered SR tubes (tubular aggregates, TAs) that do not contain myofibrils, mitochondria, nor TTs. Interestingly, TAs are also present in fast twitch muscle fibers of ageing mice. Several important issues remain un-answered: (a) the molecular mechanisms and signals that trigger the remodeling of membranes and the functional activation of SOCE during exercise are unclear; and (b) how dysfunctional SOCE and/or mutations in Stim1, Orai1 and calsequestrin (Casq1) genes lead to the formation of tubular aggregates (TAs) in aging and disease deserve investigation.
Highlights
CASQ1 Calsequestrin-1 C a2+ Entry Units (CEUs) Calcium entry unit Calcium Release Units (CRUs) Ca2+ release unit EDL Extensor digitorum longus excitation contraction (EC) Coupling Excitation–contraction coupling electron microscopy (EM) Electron microscopy endoplasmic reticulum (ER) Endoplasmic reticulum flexor digitorum brevis (FDB) Flexor digitorum brevis plasma membrane (PM) Plasma membrane Store-operated Ca2+ entry (SOCE) Store operated Ca2+ entry SR Sarcoplasmic reticulum stromal interaction molecule-1 (STIM1) Stromal interaction molecule-1
The term mechanical is used because the voltage-gated L-type C a2+ channels of transverse tubules (TTs), i.e. CaV 1.1 known as dihydropyridine receptors (DHPRs), are directly linked to the Ca2+ release channels of the SR, the ryanodine receptors type-1 (RYR1) (Block et al 1988; Paolini et al 2004; Protasi 2002)
We know that EDL and FDB fibers of Casq1-null mice contain a great amount of CEUs and their presence correlates with enhanced SOCE (Michelucci et al 2020; see “Calcium Entry Units, newly characterized intracellular SR/TT junctions that promote STIM1-ORAI1 colocalization and enhance Storeoperated Ca2+ entry”)
Summary
Store-operated Ca2+ entry (SOCE), first described as capacitative Ca2+ entry in non-excitable cells (Putney 1986), is one of main Ca2+ entry mechanisms in cells that allow the replenishment of intracellular stores, i.e. the endoplasmic reticulum (ER). Upon C a2+ depletion of internal stores, Ca2+ dissociates from the N-terminal EF-hand domains of STIM1 located in the lumen of the ER (Liou et al 2005) This leads to conformational changes with consequent dimerization of STIM1 in the ER membrane and translocation towards the PM enabling STIM1 to interact and activate ORAI1 Ca2+ channels. In non-muscle cells the process, from ER store depletion to ORAI1 channel activation, takes tens of seconds (Wu et al 2006), while in skeletal muscle some authors have proposed that Ca2+ influx can be activated very rapidly (< 1 s) following C a2+ store depletion (Edwards et al 2010; Launikonis and Rios 2007) This led some authors to conclude that the rapid activation of SOCE in muscle could be only explained by the presence of pre-formed SR-TT junctions promoting a preferential and fast access of STIM1 to ORAI1. Darbellay and colleagues discovered a Stim splice variant highly expressed in skeletal muscle, Stim1-long, that could account for rapid SOCE activation at the triad where the TTs contain ORAI1 (Darbellay et al 2009, 2011)
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