Stabilization of calcium release channel (ryanodine receptor) function by FK506-binding protein

Brillantes, Anne-Marie B.; Ondriaš, Karol; Scott, A. I.; Kobrinsky, Evgeny; Ondriašová, Elena; Moschella, Maria C.; Jayaraman, Thottala; Landers, Mark; Ehrlich, Barbara E.; Marks, Andrew R.

doi:10.1016/0092-8674(94)90214-3

Cited by 770 publications

(639 citation statements)

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“…Heterogeneity in the functional state of RyRs may explain why some preparations respond poorly to ryanodine. For example, RyRs could be refractory to ryanodine because of a lack of association with accessory proteins such as FKB506-binding protein 37 . The ryanodine-sensitive mIPSCs were organized in bursts, as revealed by a specific enhancement of interevent intervals lower than 50 ms ( Fig.…”

Section: Spontaneous Ca 2+ I Transients In Presynaptic Terminalsmentioning

confidence: 99%

Presynaptic calcium stores underlie large-amplitude miniature IPSCs and spontaneous calcium transients

et al. 2000

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articlesThe building block of synaptic transmission is the quantum, the minimal increment of postsynaptic signals 1 . At vertebrate neuromuscular junctions, the quantum may be equated with spontaneous signals obtained in the absence of presynaptic action potentials, called miniature currents (or potentials) and believed to be due to release of one neurotransmitter vesicle. For central synapses, this issue remains an open question, as large miniature currents are suggested to arise from the concerted release of several presynaptic vesicles and to be the sum of several quanta 2-5 . Such multivesicular miniature events could reflect tetrodotoxinresistant action potentials in presynaptic terminals 6 . Another explanation comes from evidence for functional intracellular Ca 2+ stores in presynaptic terminals. First, inositoltrisphosphate (InsP 3 ) receptors are immunolocalized in presynaptic terminals of the deep cerebellar nuclei and retina 7,8 . Second, at the frog neuromuscular junction, agents that affect ryanodine-sensitive Ca 2+ stores also regulate presynaptic intracellular Ca 2+ (Ca 2+ i ) rises and acetylcholine release during high-frequency stimulation 9,10 . Third, action-potential-evoked release of acetylcholine at synapses in Aplysia buccal ganglia is inhibited by ryanodine and augmented by presynaptic injection of cyclic ADP ribose 11 . Fourth, caffeine and/or ryanodine modify presynaptic Ca 2+ i signals in autonomic ganglia 12,13 and in photoreceptors 14 . Finally, in hippocampal pyramidal cells, caffeine or thapsigargin can increase the frequency of miniature IPSCs 15 . Hence, spontaneous Ca 2+ release from presynaptic Ca 2+ stores may provide the synchronization mechanism that leads to multivesicular miniatures. However, except for one study that gave negative results in cultured retinal amacrine cells 16 , this possibility has not been tested systematically.To assess the contribution of intracellular Ca 2+ stores to neurotransmitter release, we monitored the amplitude distribution of miniature synaptic currents while manipulating potential presynaptic Ca 2+ stores. Using cerebellar interneuron-Purkinje cell synapses, in which large miniature synaptic currents are prominent, we found that the largest mIPSCs result from multivesicular release and depend on Ca 2+ mobilization from ryanodine-sensitive presynaptic stores. Further, two-photon confocal microscopy showed ryanodine-sensitive intracellular Ca 2+ i transients highly localized to presumed release sites, which may underlie large miniature currents. RESULTSMiniature IPSCs recorded in cerebellar Purkinje cells, at -60 mV under symmetrical Cl -concentrations and in the presence of tetrodotoxin (TTX) and ionotropic glutamate receptor blockers, showed mean amplitudes of 125 ± 9 pA (n = 28 cells), larger than for most neurons (Fig. 1a). Amplitude histograms had a distinct peak for values less than 200 pA, followed by a long tail with amplitudes up to 1500 pA (Fig. 1b). Spurious summation of independent events did not contribute to the generation of lar...

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Section: Spontaneous Ca 2+ I Transients In Presynaptic Terminalsmentioning

confidence: 99%

Presynaptic calcium stores underlie large-amplitude miniature IPSCs and spontaneous calcium transients

et al. 2000

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“…(1) The muscle vesicles used correspond to the light fraction derived from the longitudinal sarcoplasmic reticulum, which does not contain either the Ins(1,4,5)P $ or the ryanodine Ca# + channels [28,29]. (2) Both the Ins(1,4,5)P $ and the ryanodine Ca# + channels are modulated by immunophilins that bind to FK506 and not to CsA [20][21][22][23][24][25]. Despite the antagonism produced by CsA, the effects of PMA and OAG were not inhibited by FK506.…”

Section: Discussionmentioning

confidence: 99%

“…CsA regulates only the uncoupling promoted by PMA and OAG and not that induced by other hydrophobic drugs. Although it is not known whether regulation of this effect by CsA occurs via immunophilins, it is worth noting that immunophilins have already been shown to be associated with the membrane of the sarcoplasmic reticulum of skeletal muscle and the endoplasmic reticulum of different cells [22][23][24].…”

Section: Discussionmentioning

confidence: 99%

“…Although the molecular mechanism whereby CsA and FK506 induce immunosuppression is not completely clear, it has been accepted that their mode of action depends on the conformation acquired after binding with their respective immunophilins [20,21]. Different authors have localized immunophilins to the sarcoplasmic reticulum, and the FK506-binding protein has been found to modulate both the Ins(1,4,5)P $ and ryanodine Ca# + channels [22][23][24][25]. In spite of the fact that both immunophilins and phospholipase C, which leads to the formation of diacylglycerol, have been identified in the sarcoplamic reticulum, as far as we know a possible direct effect of these agents on the Ca# + -ATPase has not been investigated before.…”

Section: Introductionmentioning

confidence: 99%

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Uncoupling of Ca2+ transport ATPase in muscle and blood platelets by diacylglycerol analogues and cyclosporin A antagonism

1997

Biochemical Journal

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The possibility that diacylglycerol analogues might have a wider spectrum of intracellular targets than the well-known protein kinase C was investigated with vesicles containing the Ca# + -ATPase derived from the dense tubular system in platelets and from the sarcoplasmic reticulum of skeletal muscle. The diacylglycerol analogues PMA and 1-oleoyl-2-acetyl-rac-glycerol (OAG) inhibited Ca# + accumulation by these vesicles, an effect that was antagonized by cyclosporin A. The inhibitory activity of PMA and OAG resulted from the uncoupling of the Ca# + -ATPase, characterized by a pronounced inhibition of Ca# + uptake accompanied by a discrete decrease in ATPase activity and by the inhibition of the enzyme's phosphorylation by P i , leading to both a decrease in ATP synthesis and an enhancement of Ca# +

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“…FKBP12-FK506/rapamycin complexes inhibit key events in the cytoplasmic signal process, leading to immunosuppression (Schreiber, 1991). FKBP12 and its isoform FKBP12.6 have been found to be crucial regulators of intracellular Ca 2+ release due to their association with ryanodine receptors, thus playing essential roles in excitation-contraction coupling in skeletal and cardiac muscle (Jayaraman et al, 1992;Brillantes et al, 1994;Xin et al, 1999;Carmody et al, 2001;Gaburjakova et al, 2001). Disruption of the FKBP12.6 gene in mice results in cardiac hypertrophy (Xin et al, 2002), while developmental cardiac defects have been reported in FKBP12-deficient mice (Shou et al, 1998).…”

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confidence: 99%

Energetic and Structural Analysis of the Role of Tryptophan 59 in FKBP12

Fulton¹,

Jackson

Buckle

2003

Biochemistry

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Tryptophan 59 forms the seat of the hydrophobic ligand-binding site in the small immunophilin FKBP12. Mutating this residue to phenylalanine or leucine stabilizes the protein by 2.72 and 2.35 kcal mol -1 , respectively. Here we report the stability data and 1.7 Å resolution crystal structures of both mutant proteins, complexed with the immunosuppressant rapamycin. Both structures show a relatively large response to mutation involving a helical bulge at the mutation site and the loss of a hydrogen bond that anchors a nearby loop. The increased stability of the mutants is probably due to a combination of improved packing and an entropic gain at the mutation site. The structures are almost identical to that of wild-type FKBP12.6, an isoform of FKBP12 that differs by 18 residues, including Trp59, in its sequence. Therefore, the structural difference between the two isoforms can be attributed almost entirely to the identity of residue 59. It is likely that in FKBP12-ligand complexes Trp59 provides added binding energy at the active site at the expense of protein stability, a characteristic common to other proteins. FKBP12 associates with the ryanodine receptor in skeletal muscle (RyR1), while FKBP12.6 selectively binds the ryanodine receptor in cardiac muscle (RyR2). The structural response to mutation suggests that residue 59 contributes to the specificity of binding between FKBP12 isoforms and ryanodine receptors.

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Stabilization of calcium release channel (ryanodine receptor) function by FK506-binding protein

Cited by 770 publications

References 68 publications

Presynaptic calcium stores underlie large-amplitude miniature IPSCs and spontaneous calcium transients

Presynaptic calcium stores underlie large-amplitude miniature IPSCs and spontaneous calcium transients

Uncoupling of Ca2+ transport ATPase in muscle and blood platelets by diacylglycerol analogues and cyclosporin A antagonism

Energetic and Structural Analysis of the Role of Tryptophan 59 in FKBP12

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