Checking your SOCCs and feet: the molecular mechanisms of Ca2+ entry in skeletal muscle - PubMed (original) (raw)

Review

Checking your SOCCs and feet: the molecular mechanisms of Ca2+ entry in skeletal muscle

Robert T Dirksen. J Physiol. 2009.

Abstract

It has long been known that skeletal muscle contraction persists in the absence of extracellular Ca(2+). Nevertheless, recent evidence indicates that multiple distinct Ca(2+) entry pathways exist in skeletal muscle: one active at negative potentials that requires store depletion (store-operated calcium entry or SOCE) and a second that is independent of store depletion and is activated by depolarization (excitation-coupled calcium entry or ECCE). This review highlights recent findings regarding the molecular identity, subcellular localization, and inter-relationship between SOCE and ECCE in skeletal muscle. The respective roles of ryanodine receptors (RyRs), dihydropyridine receptors (DHPRs), inositol-1,4,5-trisphosphate receptors (IP(3)Rs), canonical transient receptor potential channels (TRPCs), STIM1 Ca(2+) sensor proteins, and Orai1 Ca(2+) permeable channels in mediating SOCE and ECCE in skeletal muscle are discussed. Differences between SOCE and ECCE in skeletal muscle with Ca(2+) entry mechanisms in non-excitable cells are also reviewed. Finally, potential physiological roles for SOCE and ECCE in skeletal muscle development and function, as well as other currently unanswered questions and controversies in the field are also considered.

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Figures

Figure 1

Figure 1. Proposed molecular models for SOCE in skeletal muscle

A, conformational coupling between the ryanodine receptor (RyR) and canonical transient receptor potential (TRPC) channels. B, conformational coupling between inositol-1,4,5-trisphosphate (IP3) receptors and TRPC channels. C, conformational coupling between ER/SR stromal interaction molecule 1 (STIM1) Ca2+ sensor proteins and Ca2+ permeable Orai1 channels. For clarity, only one Orai1 subunit is shown.

Figure 2

Figure 2. Structural features of human STIM and Orai proteins

A, structural features of human STIM proteins. EF, Ca2+ binding EF hand domain; SAM, sterile-α-motif; TM, transmembrane domain; c-c, coiled coil domain; ERM, ezrin–radixin moesin domain; S/P serine-proline-rich domain; KKK, lysine-rich domain; CAD, channel activation domain; SOAR, STIM1–Orai activation region; P/H/E, proline-histidine-glutimate-rich domain. B, structural features of human Orai proteins. P/R, proline-arginine-rich domain; TM, transmembrane domain; c-c, coiled coil domain; SCID, severe combined immunodeficiency.

Figure 3

Figure 3. Proposed models for activation of SOCE in T-lymphocytes and skeletal muscle

A, model for activation of SOCE in T-lymphocytes. At rest (upper), Ca2+-bound STIM1 proteins are diffusely distributed in the ER and Orai1 proteins are randomly located in the plasma membrane (shown as non-functional dimer; Penna et al. 2008). Following store depletion (lower), Ca2+ unbinding from the STIM1 EF hand results in STIM1 oligomerization and redistribution into discrete puncta under the plasma membrane. Orai1 channels are recruited into these puncta and conformational coupling between STIM1 oligomers and tetrameric Orai1 channels results in activation of SOCE. B, proposed model for rapid activation of SOCE in skeletal muscle. At rest (upper), Ca2+-bound STIM1 proteins are pre-localized to the SR terminal cisternae and Orai1 proteins are located in the t-tubule membrane. Following store depletion (lower), Ca2+ unbinding from the STIM1 EF hand results in STIM1 oligomerization, recruitment of nearby Orai1 subunit, and conformational activation of SOCE. C, alternate proposed model for ultra-rapid activation of SOCE in skeletal muscle. At rest (upper), Ca2+-bound STIM1 proteins in the SR terminal cisternae are pre-bound to inactive tetrameric Orai1 channels located in the t-tubule membrane. Following store depletion (lower), Ca2+ unbinding from the STIM1 EF hand results in an immediate conformational change in the STIM1–Orai1 interaction that rapidly activates SOCE.

Figure 4

Figure 4. SOCE and ECCE muscle are determined by distinct molecular complexes within SR–sarcolemmal junctions

Left, SOCE involves ‘inside-out’ conformational coupling between SR STIM1 Ca2+ sensor proteins and tetrameric Ca2+ permeable Orai1 channels located in the t-tubule membrane. For clarity, only one Orai1 subunit is shown. Right, ECCE involves ‘outside-in’ conformational coupling between the DHPR voltage sensor and the SR Ca2+ release channel. The Ca2+ permeation pathway for ECCE involves Ca2+ flux through the L-type Ca2+ channel pore and/or an unidentified associated channel. Figure modified with permission from Lyfenko & Dirksen (2008).

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