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Article ; Online: Ryanodine receptor-mediated arrhythmias and sudden cardiac death.

Blayney, Lynda M / Lai, F Anthony

2009 Volume 123, Issue 2, Page(s) 151–177

Abstract: The cardiac ryanodine receptor-Ca2+ release channel (RyR2) is an essential sarcoplasmic reticulum (SR) transmembrane protein that plays a central role in excitation-contraction coupling (ECC) in cardiomyocytes. Aberrant spontaneous, diastolic Ca2+ leak ... ...

Abstract	The cardiac ryanodine receptor-Ca2+ release channel (RyR2) is an essential sarcoplasmic reticulum (SR) transmembrane protein that plays a central role in excitation-contraction coupling (ECC) in cardiomyocytes. Aberrant spontaneous, diastolic Ca2+ leak from the SR due to dysfunctional RyR2 contributes to the formation of delayed after-depolarisations, which are thought to underlie the fatal arrhythmia that occurs in both heart failure (HF) and in catecholaminergic polymorphic ventricular tachycardia (CPVT). CPVT is an inherited disorder associated with mutations in either the RyR2 or a SR luminal protein, calsequestrin. RyR2 shows normal function at rest in CPVT but the RyR2 dysfunction is unmasked by physical exercise or emotional stress, suggesting abnormal RyR2 activation as an underlying mechanism. Several potential mechanisms have been advanced to explain the dysfunctional RyR2 observed in HF and CPVT, including enhanced RyR2 phosphorylation status, altered RyR2 regulation at luminal/cytoplasmic sites and perturbed RyR2 intra/inter-molecular interactions. This review considers RyR2 dysfunction in the context of the structural and functional modulation of the channel, and potential therapeutic strategies to stabilise RyR2 function in cardiac pathology.
MeSH term(s)	Animals ; Arrhythmias, Cardiac/etiology ; Calcium/metabolism ; Catecholamines/metabolism ; Death, Sudden, Cardiac/etiology ; Mutation ; Myocardium/metabolism ; Phosphorylation ; Ryanodine Receptor Calcium Release Channel/genetics ; Ryanodine Receptor Calcium Release Channel/metabolism ; Sarcoplasmic Reticulum/genetics ; Sarcoplasmic Reticulum/metabolism ; Tachycardia, Ventricular/etiology ; Tachycardia, Ventricular/physiopathology
Chemical Substances	Catecholamines ; Ryanodine Receptor Calcium Release Channel ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2009-04-01
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	194735-7
ISSN	1879-016X ; 0163-7258
ISSN (online)	1879-016X
ISSN	0163-7258
DOI	10.1016/j.pharmthera.2009.03.006
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Article ; Online: A mechanism of ryanodine receptor modulation by FKBP12/12.6, protein kinase A, and K201.

Blayney, Lynda M / Jones, Jonathan-Lee / Griffiths, Julia / Lai, F Anthony

Cardiovascular research

2009 Volume 85, Issue 1, Page(s) 68–78

Abstract: Aims: Our objective was to explore the functional interdependence of protein kinase A (PKA) phosphorylation with binding of modulatory FK506 binding proteins (FKBP12/12.6) to the ryanodine receptor (RyR). RyR type 1 or type 2 was prepared from rabbit ... ...

Abstract	Aims: Our objective was to explore the functional interdependence of protein kinase A (PKA) phosphorylation with binding of modulatory FK506 binding proteins (FKBP12/12.6) to the ryanodine receptor (RyR). RyR type 1 or type 2 was prepared from rabbit skeletal muscle or pig cardiac muscle, respectively. In heart failure, RyR2 dysfunction is implicated in fatal arrhythmia and RyR1 dysfunction is associated with muscle fatigue. A controversial underlying mechanism of RyR1/2 dysfunction is proposed to be hyperphosphorylation of RyR1/2 by PKA, causing loss of FKBP12/12.6 binding that is reversible by the experimental inhibitory drug K201 (JTV519). Phosphorylation is also a trigger for fatal arrhythmia in catecholaminergic polymorphic ventricular tachycardia associated with point mutations in RyR2. Methods and results: Equilibrium binding kinetics of RyR1/2 to FKBP12/12.6 were measured using surface plasmon resonance (Biacore). Free Ca(2+) concentration was used to modulate the open/closed conformation of RyR1/2 channels measured using [(3)H]ryanodine binding assays. The affinity constant-K(A), for RyR1/2 binding to FKBP12/12.6, was significantly greater for the closed compared with the open conformation. The effect of phosphorylation or K201 was to reduce the K(A) of the closed conformation by increasing the rate of dissociation k(d). K201 reduced [(3)H]ryanodine binding to RyR1/2 at all free Ca(2+) concentrations including PKA phosphorylated preparations. Conclusion: The results are explained through a model proposing that phosphorylation and K201 acted similarly to change the conformation of RyR1/2 and regulate FKBP12/12.6 binding. K201 stabilized the conformation, whereas phosphorylation facilitated a subsequent molecular event that might increase the rate of an open/closed conformational transition.
MeSH term(s)	Animals ; Cyclic AMP-Dependent Protein Kinases/physiology ; Male ; Phosphorylation ; Protein Conformation ; Rabbits ; Ryanodine/metabolism ; Ryanodine Receptor Calcium Release Channel/chemistry ; Ryanodine Receptor Calcium Release Channel/metabolism ; Swine ; Tacrolimus Binding Protein 1A/metabolism ; Tacrolimus Binding Protein 1A/pharmacology ; Tacrolimus Binding Proteins/metabolism ; Thiazepines/pharmacology
Chemical Substances	Ryanodine Receptor Calcium Release Channel ; Thiazepines ; K201 compound (0I621Y6R4Q) ; Ryanodine (15662-33-6) ; Cyclic AMP-Dependent Protein Kinases (EC 2.7.11.11) ; Tacrolimus Binding Protein 1A (EC 5.2.1.-) ; Tacrolimus Binding Proteins (EC 5.2.1.-) ; tacrolimus binding protein 1B (EC 5.2.1.-)
Language	English
Publishing date	2009-08-03
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80340-6
ISSN	1755-3245 ; 0008-6363
ISSN (online)	1755-3245
ISSN	0008-6363
DOI	10.1093/cvr/cvp273
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Article: Physical coupling between ryanodine receptor-calcium release channels.

Yin, Chang-Cheng / Blayney, Lynda M / Lai, F Anthony

Journal of molecular biology

2005 Volume 349, Issue 3, Page(s) 538–546

Abstract: Ryanodine receptor-calcium release channels play a pivotal role in the calcium signaling that mediates muscle excitation-contraction coupling. Their membrane organization into regular patterns, functional gating studies and theoretical analysis of ... ...

Abstract	Ryanodine receptor-calcium release channels play a pivotal role in the calcium signaling that mediates muscle excitation-contraction coupling. Their membrane organization into regular patterns, functional gating studies and theoretical analysis of receptor clustering have led to models that invoke allosteric interaction between individual channel oligomers as a critical mechanism for control of calcium release. Here we show that in reconstituted "checkerboard-like" lattices that mimic in situ membrane channel arrays, each oligomer is interlocked physically with four adjacent oligomers via a specific domain-domain interaction. Direct physical coupling between ryanodine receptors provides structural evidence for an inter-oligomer allosteric mechanism in channel regulation. Therefore, in addition to established cytosolic and luminal regulation of function, these observations indicate that channel-channel communication through physical coupling provides a novel mode of regulation of intracellular calcium release channels.
MeSH term(s)	Animals ; Calcium Signaling/physiology ; Models, Molecular ; Protein Structure, Tertiary ; Rabbits ; Ryanodine Receptor Calcium Release Channel/chemistry ; Ryanodine Receptor Calcium Release Channel/metabolism ; Sarcoplasmic Reticulum/metabolism
Chemical Substances	Ryanodine Receptor Calcium Release Channel
Language	English
Publishing date	2005-06-10
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80229-3
ISSN	1089-8638 ; 0022-2836
ISSN (online)	1089-8638
ISSN	0022-2836
DOI	10.1016/j.jmb.2005.04.002
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Article: Ryanodine receptor binding to FKBP12 is modulated by channel activation state.

Jones, Jonathan-Lee / Reynolds, Deborah F / Lai, F Anthony / Blayney, Lynda M

Journal of cell science

2005 Volume 118, Issue Pt 20, Page(s) 4613–4619

Abstract: Ryanodine receptor (RyR) Ca2+ release channels undergo a conformational change between the open and closed states. Its protein modulator, FK506 binding protein 12 (FKBP12), stabilises the channel gating between the four subunits that surround a central ... ...

Abstract	Ryanodine receptor (RyR) Ca2+ release channels undergo a conformational change between the open and closed states. Its protein modulator, FK506 binding protein 12 (FKBP12), stabilises the channel gating between the four subunits that surround a central Ca2+-conducting pore. To understand the interdependence of RyR and FKBP12 binding, physiological and pharmacological agents were used to modulate the RyR open/closed state. ELISA sandwich binding assays showed that FKBP12 binding was dependent on the free Ca2+ and was lower at 1-10 microM free Ca2+ compared with 1 mM EGTA and 1 mM Ca2+, and this effect was enhanced by the inclusion of 1 mM ATP. Ruthenium red increased the binding of FKBP12. [3H]Ryanodine binding confirmed that 1 mM EGTA, 1 mM Ca2+ and 1 microM ruthenium red closed the channel, whereas 1 microM free Ca2+, 1 microM free Ca2+ + 1 mM ATP, or 10 mM caffeine opened it. These binding conditions were used in surface plasmon resonance studies to measure equilibrium binding kinetics. The affinity constant KA was significantly greater for the closed than the open channel, a change mediated by a decreased dissociation rate constant, kd. The results show that surface plasmon resonance is a powerful technique that can measure differences in RyR1 equilibrium binding kinetics with FKBP12.
MeSH term(s)	Animals ; Caffeine/pharmacology ; Enzyme-Linked Immunosorbent Assay ; Ion Channel Gating/drug effects ; Ion Channel Gating/physiology ; Rabbits ; Recombinant Fusion Proteins ; Ruthenium Red/pharmacology ; Ryanodine/metabolism ; Ryanodine Receptor Calcium Release Channel/metabolism ; Surface Plasmon Resonance ; Tacrolimus Binding Protein 1A/deficiency ; Tacrolimus Binding Protein 1A/metabolism
Chemical Substances	Recombinant Fusion Proteins ; Ryanodine Receptor Calcium Release Channel ; Ruthenium Red (11103-72-3) ; Ryanodine (15662-33-6) ; Caffeine (3G6A5W338E) ; Tacrolimus Binding Protein 1A (EC 5.2.1.-)
Language	English
Publishing date	2005-10-15
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2993-2
ISSN	1477-9137 ; 0021-9533
ISSN (online)	1477-9137
ISSN	0021-9533
DOI	10.1242/jcs.02582
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Article: Ryanodine receptor oligomeric interaction: identification of a putative binding region.

Blayney, Lynda M / Zissimopoulos, Spyros / Ralph, Emma / Abbot, Eleanor / Matthews, Laura / Lai, F Anthony

The Journal of biological chemistry

2004 Volume 279, Issue 15, Page(s) 14639–14648

Abstract: Specific interactions between adjacent ryanodine receptor (RyR) molecules to form ordered two-dimensional arrays in the membrane have been demonstrated using electron microscopy both in situ, in tissues and cells, and in vitro, with the purified protein. ...

Abstract	Specific interactions between adjacent ryanodine receptor (RyR) molecules to form ordered two-dimensional arrays in the membrane have been demonstrated using electron microscopy both in situ, in tissues and cells, and in vitro, with the purified protein. RyR interoligomeric association has also been inferred from observations of simultaneous channel gating during multi-RyR channel recordings in lipid bilayers. In this study, we report experiments designed to identify the region(s) of the RyR molecule, participating in this reciprocal interaction. Using epitope-specific antibodies, we identified a RyR tryptic fragment that specifically bound the intact immobilized RyR. Three overlapping RyR fragments encompassing this epitope, expressed using an in vitro mammalian expression system, were immunoprecipitated by RyR. To refine the binding regions, smaller RyR fragments were expressed as glutathione S-transferase (GST) fusion proteins, and their binding to RyR was monitored using a "sandwich" enzyme-linked immunosorbent assay. Three GST-RyR fusion proteins demonstrated specific binding, dependent upon ionic strength. Binding was greatest at 50-150 mm NaCl for two GST-RyR constructs, and a third GST-RyR construct demonstrated maximum binding between 150 and 450 mm NaCl. The binding at high NaCl concentration suggested involvement of a hydrophobic interaction. In silico analysis of secondary structure showed evidence of coil regions in two of these RyR fragment sequences, which might explain these data. In GST pull-down assays, these same three fragments captured RyR2, and two of them retained RyR1. These results identify a region at the center of the linear RyR (residues 2540-3207 of human RyR2) which is able to bind to the RyR oligomer. This region may constitute a specific subdomain participating in RyR-RyR interaction.
MeSH term(s)	Amino Acid Sequence ; Animals ; Binding Sites ; Dose-Response Relationship, Drug ; Electrophoresis, Polyacrylamide Gel ; Enzyme-Linked Immunosorbent Assay ; Epitopes/chemistry ; Genetic Vectors ; Glutathione Transferase/metabolism ; Humans ; Ions ; Microscopy, Electron ; Molecular Sequence Data ; Precipitin Tests ; Protein Binding ; Protein Isoforms ; Protein Structure, Secondary ; Protein Structure, Tertiary ; Recombinant Fusion Proteins/chemistry ; Recombinant Fusion Proteins/metabolism ; Recombinant Proteins/chemistry ; Ryanodine Receptor Calcium Release Channel/chemistry ; Sequence Homology, Amino Acid ; Sodium Chloride/chemistry ; Sodium Chloride/pharmacology ; Trypsin/pharmacology
Chemical Substances	Epitopes ; Ions ; Protein Isoforms ; Recombinant Fusion Proteins ; Recombinant Proteins ; Ryanodine Receptor Calcium Release Channel ; Sodium Chloride (451W47IQ8X) ; Glutathione Transferase (EC 2.5.1.18) ; Trypsin (EC 3.4.21.4)
Language	English
Publishing date	2004-01-13
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.M308014200
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Article: Ryanodine receptor binding to FKBP12 is modulated by channel activation state

Jones, Jonathan-Lee / Reynolds, Deborah F / Lai, F. Anthony / Blayney, Lynda M

Journal of cell science. 2005 Oct. 15, v. 118, no. 20

2005

Abstract: ... was lower at 1-10 [micro]M free Ca²⁺ compared with 1 mM EGTA and 1 mM Ca²⁺, and this effect was ... confirmed that 1 mM EGTA, 1 mM Ca²⁺ and 1 [micro]M ruthenium red closed the channel, whereas 1 [micro]M free ... Ca²⁺, 1 [micro]M free Ca²⁺ + 1 mM ATP, or 10 mM caffeine opened it. These binding conditions were used ...

Abstract	Ryanodine receptor (RyR) Ca²⁺ release channels undergo a conformational change between the open and closed states. Its protein modulator, FK506 binding protein 12 (FKBP12), stabilises the channel gating between the four subunits that surround a central Ca²⁺-conducting pore. To understand the interdependence of RyR and FKBP12 binding, physiological and pharmacological agents were used to modulate the RyR open/closed state. ELISA sandwich binding assays showed that FKBP12 binding was dependent on the free Ca²⁺ and was lower at 1-10 [micro]M free Ca²⁺ compared with 1 mM EGTA and 1 mM Ca²⁺, and this effect was enhanced by the inclusion of 1 mM ATP. Ruthenium red increased the binding of FKBP12. [³H]Ryanodine binding confirmed that 1 mM EGTA, 1 mM Ca²⁺ and 1 [micro]M ruthenium red closed the channel, whereas 1 [micro]M free Ca²⁺, 1 [micro]M free Ca²⁺ + 1 mM ATP, or 10 mM caffeine opened it. These binding conditions were used in surface plasmon resonance studies to measure equilibrium binding kinetics. The affinity constant K[subscript A] was significantly greater for the closed than the open channel, a change mediated by a decreased dissociation rate constant, k[subscript d]. The results show that surface plasmon resonance is a powerful technique that can measure differences in RyR1 equilibrium binding kinetics with FKBP12.
Language	English
Dates of publication	2005-1015
Size	p. 4613-4619.
Document type	Article
ZDB-ID	2993-2
ISSN	1477-9137 ; 0021-9533
ISSN (online)	1477-9137
ISSN	0021-9533
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Article: Role of phospholipase C-zeta domains in Ca2+-dependent phosphatidylinositol 4,5-bisphosphate hydrolysis and cytoplasmic Ca2+ oscillations.

Nomikos, Michail / Blayney, Lynda M / Larman, Mark G / Campbell, Karen / Rossbach, Andreas / Saunders, Christopher M / Swann, Karl / Lai, F Anthony

The Journal of biological chemistry

2005 Volume 280, Issue 35, Page(s) 31011–31018

Abstract: ... Parrington, J., Cox, L. J., Royse, J., Blayney, L. M., Swann, K., and Lai, F. A. (2002) Development (Camb ... activation of embryo development when microinjected into mammalian eggs (Saunders, C. M., Larman, M. G ... 129, 3533-3544; Cox, L. J., Larman, M. G., Saunders, C. M., Hashimoto, K., Swann, K., and Lai, F ...

Abstract	The sperm-specific phospholipase C-zeta (PLCzeta) elicits fertilization-like Ca2+ oscillations and activation of embryo development when microinjected into mammalian eggs (Saunders, C. M., Larman, M. G., Parrington, J., Cox, L. J., Royse, J., Blayney, L. M., Swann, K., and Lai, F. A. (2002) Development (Camb.) 129, 3533-3544; Cox, L. J., Larman, M. G., Saunders, C. M., Hashimoto, K., Swann, K., and Lai, F. A. (2002) Reproduction 124, 611-623). PLCzeta may represent the physiological stimulus for egg activation and development at mammalian fertilization. PLCzeta is the smallest known mammalian PLC isozyme, comprising two EF hand domains, a C2 domain, and the catalytic X and Y core domains. To gain insight into PLCzeta structure-function, we assessed the ability of PLCzeta and a series of domain-deletion constructs to cause phosphatidylinositol 4,5-bisphosphate hydrolysis in vitro and also to generate cytoplasmic Ca2+ changes in intact mouse eggs. PLCzeta and the closely related PLCdelta1 had similar K(m) values for phosphatidylinositol 4,5-bisphosphate, but PLCzeta was around 100 times more sensitive to Ca2+ than was PLCdelta1. Notably, specific phosphatidylinositol 4,5-bisphosphate hydrolysis activity was retained in PLCzeta constructs that had either EF hand domains or the C2 domain removed, or both. In contrast, Ca2+ sensitivity was greatly reduced when either one, or both, of the EF hand domains were absent, and the Hill coefficient was reduced upon deletion of the C2 domain. Microinjection into intact mouse eggs revealed that all domain-deletion constructs were ineffective at initiating Ca2+ oscillations. These data suggest that the exquisite Ca2+-dependent features of PLCzeta regulation are essential for it to generate inositol 1,4,5-trisphosphate and Ca2+ oscillations in intact mouse eggs.
MeSH term(s)	Animals ; Calcium/metabolism ; Cytoplasm/chemistry ; Cytoplasm/metabolism ; Female ; Humans ; Hydrogen-Ion Concentration ; Isoenzymes/chemistry ; Isoenzymes/genetics ; Isoenzymes/metabolism ; Mice ; Microinjections ; Molecular Sequence Data ; Oocytes/cytology ; Oocytes/physiology ; Phosphatidylinositol 4,5-Diphosphate/chemistry ; Phosphatidylinositol 4,5-Diphosphate/metabolism ; Phosphoinositide Phospholipase C ; Phospholipase C delta ; Protein Conformation ; Rats ; Recombinant Proteins/chemistry ; Recombinant Proteins/genetics ; Recombinant Proteins/metabolism ; Sequence Deletion ; Type C Phospholipases/chemistry ; Type C Phospholipases/genetics ; Type C Phospholipases/metabolism
Chemical Substances	Isoenzymes ; Phosphatidylinositol 4,5-Diphosphate ; Recombinant Proteins ; Type C Phospholipases (EC 3.1.4.-) ; PLCD1 protein, human (EC 3.1.4.11) ; PLCZ1 protein, human (EC 3.1.4.11) ; Phosphoinositide Phospholipase C (EC 3.1.4.11) ; Phospholipase C delta (EC 3.1.4.11) ; Plcd1 protein, mouse (EC 3.1.4.11) ; Plcd1 protein, rat (EC 3.1.4.11) ; Plcz1 protein, mouse (EC 3.1.4.11) ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2005-07-06
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.M500629200
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Article: Distinctive malfunctions of calmodulin mutations associated with heart RyR2-mediated arrhythmic disease.

Vassilakopoulou, Vyronia / Calver, Brian L / Thanassoulas, Angelos / Beck, Konrad / Hu, Handan / Buntwal, Luke / Smith, Adrian / Theodoridou, Maria / Kashir, Junaid / Blayney, Lynda / Livaniou, Evangelia / Nounesis, George / Lai, F Anthony / Nomikos, Michail

Biochimica et biophysica acta

2015 Volume 1850, Issue 11, Page(s) 2168–2176

Abstract: Calmodulin (CaM) is a cytoplasmic calcium sensor that interacts with the cardiac ryanodine receptor (RyR2), a large Ca(2+) channel complex that mediates Ca(2+) efflux from the sarcoplasmic reticulum (SR) to activate cardiac muscle contraction. Direct CaM ...

Abstract	Calmodulin (CaM) is a cytoplasmic calcium sensor that interacts with the cardiac ryanodine receptor (RyR2), a large Ca(2+) channel complex that mediates Ca(2+) efflux from the sarcoplasmic reticulum (SR) to activate cardiac muscle contraction. Direct CaM association with RyR2 is an important physiological regulator of cardiac muscle excitation-contraction coupling and defective CaM-RyR2 protein interaction has been reported in cases of heart failure. Recent genetic studies have identified CaM missense mutations in patients with a history of severe cardiac arrhythmogenic disorders that present divergent clinical features, including catecholaminergic polymorphic ventricular tachycardia (CPVT), long QT syndrome (LQTS) and idiopathic ventricular fibrillation (IVF). Herein, we describe how two CPVT- (N54I & N98S) and three LQTS-associated (D96V, D130G & F142L) CaM mutations result in alteration of their biochemical and biophysical properties. Ca(2+)-binding studies indicate that the CPVT-associated CaM mutations, N54I & N98S, exhibit the same or a 3-fold reduced Ca(2+)-binding affinity, respectively, versus wild-type CaM, whereas the LQTS-associated CaM mutants, D96V, D130G & F142L, display more profoundly reduced Ca(2+)-binding affinity. In contrast, all five CaM mutations confer a disparate RyR2 interaction and modulation of [(3)H]ryanodine binding to RyR2, regardless of CPVT or LQTS association. Our findings suggest that the clinical presentation of CPVT or LQTS associated with these five CaM mutations may involve both altered intrinsic Ca(2+)-binding as well as defective interaction with RyR2.
MeSH term(s)	Animals ; Calcium/metabolism ; Calmodulin/genetics ; Long QT Syndrome/etiology ; Mutation ; Ryanodine Receptor Calcium Release Channel/physiology ; Swine ; Tachycardia, Ventricular/etiology
Chemical Substances	Calmodulin ; Ryanodine Receptor Calcium Release Channel ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2015-07-09
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	60-7
ISSN	1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650 ; 0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
ISSN (online)	1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650
ISSN	0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
DOI	10.1016/j.bbagen.2015.07.001
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Article: PLC zeta: a sperm-specific trigger of Ca(2+) oscillations in eggs and embryo development.

Saunders, Christopher M / Larman, Mark G / Parrington, John / Cox, Llewellyn J / Royse, Jillian / Blayney, Lynda M / Swann, Karl / Lai, F Anthony

Development (Cambridge, England)

2002 Volume 129, Issue 15, Page(s) 3533–3544

Abstract: Upon fertilisation by sperm, mammalian eggs are activated by a series of intracellular Ca(2+) oscillations that are essential for embryo development. The mechanism by which sperm induces this complex signalling phenomenon is unknown. One proposal is that ...

Abstract	Upon fertilisation by sperm, mammalian eggs are activated by a series of intracellular Ca(2+) oscillations that are essential for embryo development. The mechanism by which sperm induces this complex signalling phenomenon is unknown. One proposal is that the sperm introduces an exclusive cytosolic factor into the egg that elicits serial Ca(2+) release. The 'sperm factor' hypothesis has not been ratified because a sperm-specific protein that generates repetitive Ca(2+) transients and egg activation has not been found. We identify a novel, sperm-specific phospholipase C, PLC zeta, that triggers Ca(2+) oscillations in mouse eggs indistinguishable from those at fertilisation. PLC zeta removal from sperm extracts abolishes Ca(2+) release in eggs. Moreover, the PLC zeta content of a single sperm was sufficient to produce Ca(2+) oscillations as well as normal embryo development to blastocyst. Our results are consistent with sperm PLC zeta as the molecular trigger for development of a fertilised egg into an embryo.
MeSH term(s)	Amino Acid Sequence ; Animals ; Benzofurans/metabolism ; Calcium Signaling/physiology ; Cloning, Molecular ; Embryonic and Fetal Development ; Fertilization/physiology ; Fluorescent Dyes/metabolism ; Imidazoles/metabolism ; Isoenzymes/chemistry ; Isoenzymes/genetics ; Isoenzymes/metabolism ; Male ; Mice ; Microinjections ; Molecular Sequence Data ; Ovum/metabolism ; Phosphoinositide Phospholipase C ; Phylogeny ; Sequence Alignment ; Spermatozoa/enzymology ; Tissue Distribution ; Type C Phospholipases/chemistry ; Type C Phospholipases/classification ; Type C Phospholipases/genetics ; Type C Phospholipases/metabolism
Chemical Substances	Benzofurans ; Fluorescent Dyes ; Imidazoles ; Isoenzymes ; fura red (149732-62-7) ; Type C Phospholipases (EC 3.1.4.-) ; Phosphoinositide Phospholipase C (EC 3.1.4.11) ; Plcz1 protein, mouse (EC 3.1.4.11)
Language	English
Publishing date	2002-08
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	90607-4
ISSN	1477-9129 ; 0950-1991
ISSN (online)	1477-9129
ISSN	0950-1991
DOI	10.1242/dev.129.15.3533
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Article ; Online: Altered RyR2 regulation by the calmodulin F90L mutation associated with idiopathic ventricular fibrillation and early sudden cardiac death.

Nomikos, Michail / Thanassoulas, Angelos / Beck, Konrad / Vassilakopoulou, Vyronia / Hu, Handan / Calver, Brian L / Theodoridou, Maria / Kashir, Junaid / Blayney, Lynda / Livaniou, Evangelia / Rizkallah, Pierre / Nounesis, George / Lai, F Anthony

FEBS letters

2014 Volume 588, Issue 17, Page(s) 2898–2902

Abstract: Calmodulin (CaM) association with the cardiac muscle ryanodine receptor (RyR2) regulates excitation-contraction coupling. Defective CaM-RyR2 interaction is associated with heart failure. A novel CaM mutation (CaM(F90L)) was recently identified in a ... ...

Abstract	Calmodulin (CaM) association with the cardiac muscle ryanodine receptor (RyR2) regulates excitation-contraction coupling. Defective CaM-RyR2 interaction is associated with heart failure. A novel CaM mutation (CaM(F90L)) was recently identified in a family with idiopathic ventricular fibrillation (IVF) and early onset sudden cardiac death. We report the first biochemical characterization of CaM(F90L). F90L confers a deleterious effect on protein stability. Ca(2+)-binding studies reveal reduced Ca(2+)-binding affinity and a loss of co-operativity. Moreover, CaM(F90L) displays reduced RyR2 interaction and defective modulation of [(3)H]ryanodine binding. Hence, dysregulation of RyR2-mediated Ca(2+) release via aberrant CaM(F90L)-RyR2 interaction is a potential mechanism that underlies familial IVF.
MeSH term(s)	Binding Sites ; Calcium/metabolism ; Calmodulin/chemistry ; Calmodulin/genetics ; Calmodulin/metabolism ; Death, Sudden, Cardiac ; Humans ; Models, Molecular ; Mutation ; Protein Conformation ; Ryanodine Receptor Calcium Release Channel/metabolism ; Sarcoplasmic Reticulum/metabolism ; Ventricular Fibrillation/genetics
Chemical Substances	Calmodulin ; Ryanodine Receptor Calcium Release Channel ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2014-08-25
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	212746-5
ISSN	1873-3468 ; 0014-5793
ISSN (online)	1873-3468
ISSN	0014-5793
DOI	10.1016/j.febslet.2014.07.007
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