Author/Year | RYR1 variant(s) | Title | Conclusions |
---|---|---|---|
Dyspedic myotubes | |||
Lefebvre R et al. [86] 2013 | R4892W, G4896V | Ca2+ release in muscle fibers expressing R4892W and G4896V type 1 ryanodine receptor disease mutants | The dominant-negative effect of the R4892W mutant on voltage-gated Ca2+ release in myotubes and adult muscle fibers was considerably less than that observed for G4896V |
Groom L, et al. [87] 2011 | R3983C, D4505H | Identical de novo mutation in the type 1 ryanodine receptor gene associated with fatal, stress-induced malignant hyperthermia in two unrelated families | The functional impact of the two variants expressed in RyR1-nullmyotubes depends on whether the two variants are located on common or separate subunits |
Booms P, et al. [88] 2009 | E2347del | Concentration dependence of caffeine-induced Ca2+ release in dyspedic skeletal myotubes transfected with ryanodine receptor isoform-1 (RYR1) cDNAs | E2347del increases the sensitivity of RyR1 to caffeine |
Yang T, et al. [89] 2007 | R164C, R165C, R2163C, T4825I | Elevated resting [Ca(2+)](i) in myotubes expressing malignant hyperthermia RyR1 cDNAs is partially restored by modulation of passive calcium leak from the SR | Myotubes expressing any of the four MH RyR1s (at least 1 from all 3 mutation hot spots) had a higher resting [Ca2+] than those expressing WTRyR1 The elevated resting [Ca2+]i observed in myotubes expressing the four MHRyR1s varied among the individual mutations Treatment of myotubes expressing WT/MHRyR1s with ryanodine or FLA 365 had no effect on resting [Ca2+] Incubation of myotubes with bastadin 5 or ryanodine and bastadin 5 in combination significantly lowered resting [Ca2+]i in myotubes expressing either WTRyR1 and MHRyR1s The percent decrease in resting [Ca2+]i after treatment with bastadin 5 or the combination of ryanodine and bastadin 5 in myotubes expressing MHRyR1s was significantly greater than in myotubes expressing WTRyR1s |
Yang T, et al. [90] 2007 | R615C, R2163C, T48261 | Enhanced excitation-coupled calcium entry in myotubes is associated with expression of RyR1 malignant hyperthermia mutations | RyR1 MH mutations are associated with an enhanced Ca2+ entry through the sarcolemma during depolarization Ca2+ entry may contribute to maintaining Ca2+ homeostasis in mammalian skeletal EC coupling and may play an important role in the pathophysiology of malignant hyperthermia |
Goonasekera SA, et al. [91] 2007 | D4878A, D4907A, E4908A | Triadin binding to the C-terminal luminal loop of the ryanodine receptor is important for skeletal muscle excitation contraction coupling | triadin binding to RyR1 enhances release channel activity during both voltage and ligand activation and that this critical regulation of release channel activity ensures robust and rapid calcium release during skeletal muscle EC coupling |
Lyfenko AD, et al. [66] 2007 | R4214_F4216del, V4927_I4928del | Two central core disease (CCD) deletions in the C-terminal region of RYR1 alter muscle excitation-contraction (EC) coupling by distinct mechanisms | R4214_F4216del promotes Ca2+ depletion from intracellular stores by exhibiting a classic “leaky channel” behavior V4927_I4928del deletion reduces Ca2+ release by disrupting Ca2+ gating and eliminating Ca2+ permeation through the open channel |
Lee EH, et al. [92] 2006 | D4878A, D4907A, E4908A | Occurrence of atypical Ca2+ transients in triadin-binding deficient-RYR1 mutants | There was similarly atypical Ca2+ transients in response to caffeine in myotubes expressing all 3 mutations and the single mutant (D4907A) Differences in triadin-binding and SR Ca2+ release observed in this study can be attributed to an alteration in a single amino acid (D4907) |
Aracena-Parks P, et al. [93] 2006 | C3635A | Identification of cysteines involved in S-nitrosylation, S-glutathionylation, and oxidation to disulfides in ryanodine receptor type 1 | 12 of the 100 cysteines on RyR1 can be redox-modified and that 9 of these cysteines appear to be endogenously modified to some extent We also show that the different redox agents target some of the same cysteines, but Cys-1040 and Cys-1303 are exclusively S-nitrosylated, whereas Cys-1591 and Cys-3193 are exclusively S-glutathionylated On the other hand, Cys-3635 can be S-nitrosylated, S-glutathionylated, or oxidized to form a disulfide and also influences Ca2+ release during EC coupling |
Hurne AM, et al. [94] 2005 | C4958S, C4961S | Ryanodine receptor type 1 (RyR1) mutations C4958S and C4961S reveal excitation-coupled calcium entry (ECCE) is independent of sarcoplasmic reticulum store depletion | There is an essential role of Cys(4958) and Cys(4961) within an invariant CXXC motif for stabilizing conformations of RyR1 that influence both its function as a release channel and its interaction with ECCE channels |
Cheng W, et al. [95] 2005 | D3490_N3523del | Interaction between the dihydropyridine receptor Ca2+ channel β-subunit and ryanodine receptor type 1 strengthens excitation-contraction coupling | EC coupling in skeletal muscle involves the interplay of at least two subunits of the DHPR, namely alpha1S and beta1a, interacting with possibly different domains of RyR1 |
Du GG, et al. [96] 2004 | 4274_4535del | Role of the sequence surrounding predicted transmembrane helix M4 in membrane association and function of the Ca(2+) release channel of skeletal muscle sarcoplasmic reticulum (ryanodine receptor isoform 1) | Maximal amplitudes of L-currents and Ca2+ transients with Delta4274–4535 were larger than with wild-type RyR1, and voltage-gated sarcoplasmic reticulum Ca2+ release was more sensitive to activation by sarcolemmal voltage sensors Thus, this region may act as a negative regulatory module that increases the energy barrier for Ca2+ release channel opening |
Dirksen RT, et al. [97] 2004 | Y4795C, R2435L, R2163H | Distinct effects on Ca2+ handling caused by malignant hyperthermia and central core disease mutations in RyR1 | MH-only mutations modestly increase basal release-channel activity in a manner insufficient to alter net SR Ca2+ content (“compensated leak”), whereas the mixed MH + CCD phenotype arises from mutations that enhance basal activity to a level sufficient to promote SR Ca2+ depletion, elevate [Ca2+], and reduce maximal VGCR (“decompensated leak”) |
Zhu X, et al. [98] 2004 | 3614_3643del | The calmodulin binding region of the skeletal ryanodine receptor acts as a self-modulatory domain | Depolarization-, caffeine- and 4-chloro-m-cresol (4-CmC)-induced Ca2+ transients in these cells were dramatically reduced compared with cells expressing WT RyR1. Deletion of the 3614–3643 region resulted in profound changes in unitary conductance and channel gating RyR1 3614–3643 region acts not only as the CaM binding site, but also as an important modulatory domain for RyR1 function |
Yang T, et al. [99] 2003 | R163C, G341R, R614C, R2163C, V2168M, R2458H, T4826I | Functional defects in six ryanodine receptor isoform-1 (RyR1) mutations associated with malignant hyperthermia and their impact on skeletal excitation-contraction coupling | These 7 MH mutations are all both necessary and sufficient to induce MH-related phenotypes Decreased sensitivity to Ca2+ and Mg2+ inhibition and inability of MHRyR1s to be fully inactivated at [Ca2+] typical of normal myotubes at rest are key defects that contribute to the initiation of MH episodes |
Avila G, et al. [100] 2003 | Y523S, Y4795C, I4897T, G4890R, R4892W, G4898E, G4898R, A4905V, R4913G | The pore region of the skeletal muscle ryanodine receptor is a primary locus for excitation-contraction uncoupling in central core disease | CCD mutations in exon 102 disrupt release channel permeation to Ca2+ during EC coupling and that this region represents a primary molecular locus for EC uncoupling in CCD |
Avila G, et al. [101] 2003 | V2461G, V2461I | FKBP12 binding to RyR1 modulates excitation-contraction coupling in mouse skeletal myotubes | None of the mutations that disrupted FKBP binding to RyR1 significantly affected RyR1-mediated enhancement of L-type Ca2+ channel activity (retrograde coupling) FKBP12 binding to RyR1 enhances the gain of skeletal muscle EC coupling |
O’Connell KM, et al. [102] 2002 | L3624D, W3620A | Calmodulin binding to the 3614–3643 region of RyR1 is not essential for excitation-contraction coupling in skeletal myotubes | Expression of either L3624D or W3620A in dyspedic myotubes restored both L-type Ca2+ currents (retrograde coupling) and voltage-gated SR Ca2+ release (orthograde coupling) to a similar degree as that observed for wild-type RyR1, although L-current density was somewhat larger and activated at more hyperpolarized potentials in W3620A-expressing myotubes CaM binding to the 3614–3643 region of RyR1 is not essential for voltage sensor activation of RyR1 |
O’Brien JJ, et al. [103] 2002 | E4032A | Ca2+ activation of RyR1 is not necessary for the initiation of skeletal-type excitation-contraction coupling | Depolarization of E4032A-RyR1-expressing myotubes elicited L-type Ca2+ currents of approximately normal size and myoplasmic Ca2+ transients that were skeletal-type, but about fivefold smaller than those for wild-type RyR1 The reduced amplitude of the Ca2+ transient is consistent either with the possibility that Ca2+ activation amplifies Ca2+ release during EC coupling, or that the E4032A mutation generally inhibits activation of RyR1 Ca2+ activation of RyR1 does not appear to be necessary for the initiation of Ca2+ release during EC coupling in skeletal muscle |
Feng W, et al. [104] 2002 | F1777R, F1782R | Homer regulates gain of ryanodine receptor type 1 channel complex | 1B5 dyspedic myotubes expressing RyR1 with a point mutation of a putative Homer-binding domain exhibit significantly reduced (approximately 33%) amplitude in their responses to K+ depolarization compared with cells expressing wild type protein These results reveal that in addition to its known role as an adapter protein, Homer is a direct modulator of Ca2+ release gain |
Fessenden JD, et al. [105] 2001 | E4032A | Ryanodine receptor point mutant E4032A reveals an allosteric interaction with ryanodine | Results with the E4032A mutant channel suggest that ryanodine does not act as a pore blocker but instead, that ryanodine binding sites reside outside of the permeation pore, and that ryanodine binding to these sites has allosteric effects on calcium permeability |
Avila G, et al. [106] 2001 | E4032A | Ca2+ release through ryanodine receptors regulates skeletal muscle L-type Ca2+ channel expression | Long-term expression of E4032A, a mutant RyR-1 that preferentially affects the orthograde signal of E-C coupling (i.e., fully restores L-channel activity but not SR Ca2+ release) failed to increase functional DHPR expression |
Avila G, et al. [107] 2001 | I4897T | Excitation - Contraction uncoupling by a human central core disease mutation in the ryanodine receptor | Muscle weakness suffered by individuals possessing the I4898T mutation involves a functional uncoupling of sarcolemmal excitation from SR Ca2+ release, rather than the expression of overactive or leaky SR Ca2+ release channel |
Avila G, et al. [108] 2001 | R164C, I404M, Y523S, R2163H, R2435H | Functional effects of central core disease mutations in the cytoplasmic region of the skeletal muscle ryanodine receptor | Resting Ca2+ levels were elevated in dyspedic myotubes expressing four of these mutants (Y523S > R2163H > R2435H R164C > I404M RyR1) |