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STAC proteins: The missing link in skeletal muscle EC coupling and new regulators of calcium channel function

Published on Jul 1, 2019in Biochimica et Biophysica Acta: Bioenergetics4.441
· DOI :10.1016/j.bbamcr.2018.12.004
Bernhard E. Flucher37
Estimated H-index: 37
,
Marta Campiglio8
Estimated H-index: 8
Sources
Abstract
Abstract Excitation-contraction coupling is the signaling process by which action potentials control calcium release and consequently the force of muscle contraction. Until recently, three triad proteins were known to be essential for skeletal muscle EC coupling: the voltage-gated calcium channel CaV1.1 acting as voltage sensor, the SR calcium release channel RyR1 representing the only relevant calcium source, and the auxiliary CaV β1a subunit. Whether CaV1.1 and RyR1 are directly coupled or whether their interaction is mediated by another triad protein is still unknown. The recent identification of the adaptor protein STAC3 as fourth essential component of skeletal muscle EC coupling prompted vigorous research to reveal its role in this signaling process. Accumulating evidence supports its possible involvement in linking CaV1.1 and RyR1 in skeletal muscle EC coupling, but also indicates a second, much broader role of STAC proteins in the regulation of calcium/calmodulin-dependent feedback regulation of L-type calcium channels.
  • References (71)
  • Citations (3)
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References71
Newest
#1I. ZaharievaH-Index: 10
#2Anna Sarkozy (GOSH: Great Ormond Street Hospital)H-Index: 31
Last. Francesco Muntoni (GOSH: Great Ormond Street Hospital)H-Index: 99
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: SH3 and cysteine-rich domain-containing protein 3 (STAC3) is an essential component of the skeletal muscle excitation-contraction coupling (ECC) machinery, though its role and function are not yet completely understood. Here, we report 18 patients carrying a homozygous p.(Trp284Ser) STAC3 variant in addition to a patient compound heterozygous for the p.(Trp284Ser) and a novel splice site change (c.997-1G > T). Clinical severity ranged from prenatal onset with severe features at birth, to a mil...
3 CitationsSource
: Excitation-contraction (EC) coupling in skeletal muscles operates through a physical interaction between the dihydropyridine receptor (DHPR), acting as a voltage sensor, and the ryanodine receptor (RyR1), acting as a calcium release channel. Recently, the adaptor protein SH3 and cysteine-rich containing protein 3 (STAC3) has been identified as a myopathy disease gene and as an additional essential EC coupling component. STAC3 interacts with DHPR sequences including the critical EC coupling dom...
2 CitationsSource
#1Alexander PolsterH-Index: 6
#2Phillip J. Dittmer (University of Colorado Denver)H-Index: 1
Last. Kurt G. BeamH-Index: 49
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Stac protein (named for its SH3 and cysteine rich domains) was first identified in brain 20 years ago, and is currently known to have three isoforms. Stac2, Stac1 and Stac3 transcripts are found at high, modest and very low levels, respectively, in the cerebellum and forebrain, but their neuronal functions have been little investigated. Here, we tested the effects of Stac proteins on neuronal, high-voltage-activated Ca 2+ channels. Over-expression of the three Stac isoforms eliminated Ca 2+ -dep...
4 CitationsSource
#1Pierre Costé de Bagneaux (Innsbruck Medical University)H-Index: 3
#2Marta Campiglio (Innsbruck Medical University)H-Index: 8
Last. Bernhard E. Flucher (Innsbruck Medical University)H-Index: 37
view all 5 authors...
ABSTRACTVoltage-dependent calcium channels (CaV) activate over a wide range of membrane potentials, and the voltage-dependence of activation of specific channel isoforms is exquisitely tuned to their diverse functions in excitable cells. Alternative splicing further adds to the stunning diversity of gating properties. For example, developmentally regulated insertion of an alternatively spliced exon 29 in the fourth voltage-sensing domain (VSD IV) of CaV1.1 right-shifts voltage-dependence of acti...
3 CitationsSource
#1Jacqueline Niu (Johns Hopkins University)H-Index: 4
#2Ivy E. Dick (UMB: University of Maryland, Baltimore)H-Index: 2
Last. Manu Ben-Johny (Columbia University)H-Index: 8
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: Calmodulin (CaM) serves as a pervasive regulatory subunit of CaV1, CaV2, and NaV1 channels, exploiting a functionally conserved carboxy-tail element to afford dynamic Ca2+-feedback of cellular excitability in neurons and cardiomyocytes. Yet this modularity counters functional adaptability, as global changes in ambient CaM indiscriminately alter its targets. Here, we demonstrate that two structurally unrelated proteins, SH3 and cysteine-rich domain (stac) and fibroblast growth factor homologous...
6 CitationsSource
#1Jacqueline Niu (Johns Hopkins University)H-Index: 4
#2Wanjun Yang (Johns Hopkins University)H-Index: 9
Last. Manu Ben-Johny (Columbia University)H-Index: 8
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Ca V 1.1 is essential for skeletal muscle excitation–contraction coupling. Its functional expression is tuned by numerous regulatory proteins, yet underlying modulatory mechanisms remain ambiguous as Ca V 1.1 fails to function in heterologous systems. In this study, by dissecting channel trafficking versus gating, we evaluated the requirements for functional Ca V 1.1 in heterologous systems. Although coexpression of the auxiliary β subunit is sufficient for surface–membrane localization, this ba...
3 CitationsSource
#1Alexander Polster (University of Colorado Denver)H-Index: 6
#2Benjamin R. Nelson (UTSW: University of Texas Southwestern Medical Center)H-Index: 9
Last. Kurt G. Beam (University of Colorado Denver)H-Index: 49
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In skeletal muscle, residues 720–764/5 within the Ca V 1.1 II–III loop form a critical domain that plays an essential role in transmitting the excitation–contraction (EC) coupling Ca 2+ release signal to the type 1 ryanodine receptor (RyR1) in the sarcoplasmic reticulum. However, the identities of proteins that interact with the loop and its critical domain and the mechanism by which the II–III loop regulates RyR1 gating remain unknown. Recent work has shown that EC coupling in skeletal muscle o...
12 CitationsSource
#1Fenfen Wu (UCLA: University of California, Los Angeles)H-Index: 14
#2Marbella Quinonez (UCLA: University of California, Los Angeles)H-Index: 8
Last. Stephen C. Cannon (UCLA: University of California, Los Angeles)H-Index: 44
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Mutations of Ca V 1.1, the pore-forming subunit of the L-type Ca 2+ channel in skeletal muscle, are an established cause of hypokalemic periodic paralysis (HypoPP). However, functional assessment of HypoPP mutant channels has been hampered by difficulties in achieving sufficient plasma membrane expression in cells that are not of muscle origin. In this study, we show that coexpression of Stac3 dramatically increases the expression of human Ca V 1.1 (plus α 2 -δ 1b and β 1a subunits) at the plasm...
8 CitationsSource
The adaptor proteins STAC1, STAC2, and STAC3 represent a newly identified family of regulators of voltage-gated calcium channel (CaV) trafficking and function. The skeletal muscle isoform STAC3 is essential for excitation–contraction coupling and its mutation causes severe muscle disease. Recently, two distinct molecular domains in STAC3 were identified, necessary for its functional interaction with CaV1.1: the C1 domain, which recruits STAC proteins to the calcium channel complex in skeletal mu...
12 CitationsSource
The concept of excitation–contraction coupling is almost as old as Journal of General Physiology . It was understood as early as the 1940s that a series of stereotyped events is responsible for the rapid contraction response of muscle fibers to an initial electrical event at the surface. These early developments, now lost in what seems to be the far past for most young investigators, have provided an endless source of experimental approaches. In this Milestone in Physiology, I describe in detail...
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Cited By3
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CaV1.1 is specifically expressed in skeletal muscle where it functions as voltage sensor of skeletal muscle excitation-contraction (EC) coupling independently of its functions as L-type calcium channel. Consequently, all known CaV1.1-related diseases are muscle diseases and the molecular and cellular disease mechanisms relate to the dual functions of CaV1.1 in this tissue. To date, four types of muscle diseases are known that can be linked to mutations in the CACNA1S gene or to splicing defects....
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#1Dmitry Shishmarev (ANU: Australian National University)H-Index: 6
Excitation-contraction coupling (ECC) is a physiological process that links excitation of muscles by the nervous system to their mechanical contraction. In skeletal muscle, ECC is initiated with an action potential, generated by the somatic nervous system, which causes a depolarisation of the muscle fibre membrane (sarcolemma). This leads to a rapid change in the transmembrane potential, which is detected by the voltage-gated Ca2+ channel dihydropyridine receptor (DHPR) embedded in the sarcolemm...
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The skeletal muscle and myocardial cells present highly specialized structures; for example, the close interaction between the sarcoplasmic reticulum (SR) and mitochondria—responsible for excitation-metabolism coupling—and the junction that connects the SR with T-tubules, critical for excitation-contraction (EC) coupling. The mechanisms that underlie EC coupling in these two cell types, however, are fundamentally distinct. They involve the differential expression of Ca2+ channel subtypes: CaV1.1...
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#1Viktor Yarotskyy (UTHSC: University of Tennessee Health Science Center)H-Index: 1
#2John Malysz (UTHSC: University of Tennessee Health Science Center)H-Index: 1
Last. Georgi Petkov (UTHSC: University of Tennessee Health Science Center)H-Index: 1
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Cl- channels serve as key regulators of smooth muscle excitability and contractility in vascular, intestinal, and airway cells. We recently reported Cl- conductance in detrusor smooth muscle (DSM) ...
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#1Jan B. Parys (Katholieke Universiteit Leuven)H-Index: 52
#2Andreas H. Guse (UHH: University of Hamburg)H-Index: 31
Intracellular calcium (Ca2+) signals are of prime importance for cellular function and behavior and are underpinned by a plethora of Ca2+ channels, pumps, transporters, and binding proteins that are regulated in complex ways. A series of biennial meetings, the International Meetings of the European Calcium Society (ECS), focuses on a better understanding of these complex mechanisms in the framework of cellular and organismal (patho)physiology.
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#1Senthilkumar Sadhasivam (IU: Indiana University)
#2Barbara W. Brandom (University of Pittsburgh)H-Index: 29
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: Aim: Identify variants in RYR1, CACNA1S and STAC3, and predict malignant hyperthermia (MH) pathogenicity using Bayesian statistics in individuals clinically treated as MH susceptible (MHS). Materials & methods: Whole exome sequencing including RYR1, CACNA1S and STAC3 performed on 64 subjects with: MHS; suspected MH event or first-degree relative; and MH negative. Variant pathogenicity was estimated using in silico analysis, allele frequency and prior data to calculate Bayesian posterior probab...
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#2Marta CampiglioH-Index: 8
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ABSTRACTThe voltage-gated calcium channel CaV1.1a primarily functions as voltage-sensor in skeletal muscle excitation-contraction (EC) coupling. In embryonic muscle the splice variant CaV1.1e, which lacks exon 29, additionally function as a genuine L-type calcium channel. Because previous work in most laboratories used a CaV1.1 expression plasmid containing a single amino acid substitution (R165K) of a critical gating charge in the first voltage-sensing domain (VSD), we corrected this substituti...
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