RYR tetramers transport Ca2+ from sarcoplasmic reticulum lumen to cytosol

Stable Identifier
Reaction [transition]
Homo sapiens
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Ryanodine receptors (RYRs) are located in the sarcoplasmic reticulum (SR) membrane and mediate the release of Ca2+ from intracellular stores during excitation-contraction (EC) coupling in both cardiac and skeletal muscle. RYRs are the largest known ion channels (>2MDa) and are functional in their homotetrameric forms. There are three mammalian isoforms (RYR1-3); RYR1 is prominent in skeletal muscle (Zorzato et al. 1990), RYR2 in cardiac muscle (Tunwell et al. 1996) and RYR3 is found in the brain (Nakashima et al. 1997, Lanner et al. 2010). The function of RYRs are controlled by peptidyl-prolyl cis-trans isomerase (FKBP1B), intracellular Ca2+-binding proteins calsequestrin 1 and 2 (CASQ1 and 2) and the anchoring proteins triadin (TRDN) and junctin. Together, they make up the Ca2+-release complex. CASQ1 and 2 buffer intra-SR Ca2+ stores in skeletal muscle and cardiac muscle respectively (Fujii et al. 1990, Kim et al. 2007). When Ca2+ concentrations reach 1mM, CASQs polymerise (Kim et al. 2007) and can attach to one end of RYRs, mediated by anchoring proteins TRDN and junctin (Taske et al. 1995). By sequestering Ca2+ ions, CASQs can inhibit RYRs function (Beard et al. 2004, Beard et al. 2009a, Beard et al. 2009b).

A member of the intracellular Cl- channel protein family, CLIC2, has also been determined to inhibit RYR-mediated Ca2+ transport (Board et al. 2004), potentially playing a role in the homeostasis of Ca2+ release from intracellular stores. Inhibition is thought to be via reducing activation of the channels by their primary endogenous cytoplasmic ligands, ATP and Ca2+ (Dulhunty et al. 2005). Protein kinase A (PKA) phosphorylation of RYR2 dissociates FKBP1B and results in defective channel function (Marx et al. 2000). The penta-EF hand protein sorcin (SRI) can modulate Ca2+-induced calcium-release in the heart via the interaction with several Ca2+ channels such as RYRs. A natural ligand, F112L, impairs this modulating activity (Franceschini et al. 2008). Calmodulin (CALM1) is considered a gatekeeper of RYR2. CALM1 acts directly by binding to RYR2 at residues 3583–3603, inhibiting RYR2 both at physiological and higher, pathological Ca2+ concentrations (Smith et al. 1989, Ono et al. 2010).
Literature References
PubMed ID Title Journal Year
2321095 Characterization and localization to human chromosome 1 of human fast-twitch skeletal muscle calsequestrin gene

Fujii, J, MacLennan, DH, Willard, HF

Somat. Cell Mol. Genet. 1990
9395096 Molecular cloning and characterization of a human brain ryanodine receptor

Nishimura, S, Kita, T, Nakashima, Y, Imoto, K, Allen, PD, Nakai, J, Barsoumian, EL, Hakamata, Y, Maeda, A

FEBS Lett. 1997
17699613 Molecular basis for the impaired function of the natural F112L sorcin mutant: X-ray crystal structure, calcium affinity, and interaction with annexin VII and the ryanodine receptor

Antaramian, A, Verzili, D, Rueda, A, Valdivia, HH, Zamparelli, C, Franceschini, S, Chiancone, E, Ilari, A, Colotti, G

FASEB J. 2008
15916532 A recently identified member of the glutathione transferase structural family modifies cardiac RyR2 substate activity, coupled gating and activation by Ca2+ and ATP

Dulhunty, AF, Pouliquin, P, Coggan, M, Board, PG, Gage, PW

Biochem. J. 2005
15147738 CLIC-2 modulates cardiac ryanodine receptor Ca2+ release channels

Dulhunty, AF, Watson, S, Coggan, M, Gage, PW, Board, PG

Int. J. Biochem. Cell Biol. 2004
17881003 Characterization of human cardiac calsequestrin and its deleterious mutants

Kang, C, Campbell, C, Kemper, L, Varsanyi, M, Milting, H, Kim, E, Youn, B

J. Mol. Biol. 2007
2298749 Molecular cloning of cDNA encoding human and rabbit forms of the Ca2+ release channel (ryanodine receptor) of skeletal muscle sarcoplasmic reticulum

Otsu, K, Fujii, J, Zorzato, F, Meissner, G, MacLennan, DH, Green, NM, Lai, FA, Phillips, M

J. Biol. Chem. 1990
8809036 The human cardiac muscle ryanodine receptor-calcium release channel: identification, primary structure and topological analysis

Shevchenko, VI, Walsh, MB, Bertrand, BM, Tunwell, RE, Allen, PD, Wickenden, C, Lai, FA

Biochem. J. 1996
20388639 Dissociation of calmodulin from cardiac ryanodine receptor causes aberrant Ca(2+) release in heart failure

Ono, M, Tateishi, H, Xu, X, Oda, T, Uchinoumi, H, Yano, M, Okuda, S, Hino, A, Ikemoto, N, Doi, M, Susa, T, Kobayashi, S, Yamamoto, T, Suetomi, T, Matsuzaki, M, Kyushiki, H, Koseki, N

Cardiovasc. Res. 2010
2536303 Calmodulin modulation of single sarcoplasmic reticulum Ca2+-release channels from cardiac and skeletal muscle

Smith, JS, Meissner, G, Rousseau, E

Circ. Res. 1989
10830164 PKA phosphorylation dissociates FKBP12.6 from the calcium release channel (ryanodine receptor): defective regulation in failing hearts

Burkhoff, D, Rosemblit, N, Hisamatsu, Y, Marks, AR, Jayaraman, T, Marx, SO, Reiken, S

Cell 2000
7588753 Molecular cloning of the cDNA encoding human skeletal muscle triadin and its localisation to chromosome 6q22-6q23

Foster, PS, Taske, NL, Eyre, HJ, Sutherland, GR, Denborough, MA, O'Brien, RO

Eur. J. Biochem. 1995
Catalyst Activity

calcium-induced calcium release activity of RYR tetramer:FKBP1B tetramer:CASQ polymer:TRDN:junctin [sarcoplasmic reticulum membrane]

This event is regulated
Orthologous Events
Cross References
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