Effects of an α-helical ryanodine receptor C-terminal tail peptide on ryanodine receptor activity: Modulation by Homer

Pouliquin, Pierre; Pace, Suzy M.; Curtis, Suzanne M.; Harvey, Peta J.; Gallant, Esther M.; Zorzato, Francesco; Dulhunty, Angela F.

doi:10.1016/j.biocel.2006.03.020

Cited by 13 publications

(18 citation statements)

References 43 publications

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“…[11]), and the H1b effect on RyR1 is also consistent with previous results [9,10,14,20,26]. This is the first report of RyR2 activation by H1b or any other Homer isoform.…”

Section: Resultssupporting

confidence: 93%

“…1b). H1b expressed and purified this way has been used successively to study Homer effects on RyR1 activity in vitro [9,20]. In control experiments, RyR2 activity was unaffected by 0-1 μM 6His Ubiquitin (data not shown).…”

Section: Resultsmentioning

confidence: 91%

“…2, [9,10,14,20]) have established that the long isoforms of Homer1 activate RyR1 in vitro. Recently, Feng et al showed that the effect on RyR1 is in fact biphasic: with Homer1c ≤50 nM activating RyR1, while higher concentrations decreased activity [9].…”

Section: Discussionmentioning

confidence: 98%

“…Homer Human Homer1b (H1b) fusion protein (with C-myc and 6His tags) was expressed and purified as previously [20]. The sequence encoding the human Homer1b 120 Nterminal residues (short Homer, ShoHo) was amplified by polymerase chain reaction and subcloned into the plasmid pHUE [4] and was expressed and purified in the same way as H1b.…”

Section: Methodsmentioning

confidence: 99%

“…Both Homer1b and Homer1c activate the skeletal muscle RyR1 at low concentrations [10,14,20,26] but inhibit RyR1 at higher concentrations [9]. Short Homer1 has also been shown to modulate RyR1 in a similar way although with lower affinity [9,26]; one group found no direct effect of short Homer1 on RyR1 activity [14].…”

Section: Introductionmentioning

confidence: 94%

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In vitro modulation of the cardiac ryanodine receptor activity by Homer1

Pouliquin

Pace

Dulhunty

2009

Pflugers Arch - Eur J Physiol

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The Homer protein family allows clustering and/or functional modulation of many proteins from different calcium signalling complexes including those formed by the ryanodine receptor (RyR) Ca(2+) release channel in skeletal muscle and the heart. Homer1b/c and the cardiac RyR (RyR2) are strongly expressed in the heart and neurons where their interaction with each other may modulate Ca(2+) signalling. However, functional interactions between Homer1b and RyR2 have been poorly defined. Our preliminary data and similar consensus binding sites for Homer in RyR2 and skeletal RyR (RyR1) proteins, led to the hypothesis that Homer may similarly regulate both RyR isoforms. Single-channel and [(3)H]ryanodine binding data showed that RyR2 and RyR1 activity increased to a maximum with ~50-100 nM Homer1b and fell with Homer1b > 200 nM. Homer1b (50 nM) activated RyR2 and RyR1 at all cytosolic [Ca(2+)]; estimated EC(50) value of RyR2 diminished from ~2.8 microM Ca(2+) (control) to ~1.9 microM Ca(2+) in the presence of 50 nM Homer1b. Short Homer1 (lacking the coiled-coil multimerisation domain) and Homer1b similarly modulated RyR2, indicating an action through ligand binding, not mutimerisation. These actions of Homer were generally similar in RyR2 and RyR1. The strong functional interactions suggest that Homer1 is likely to be an endogenous modulator of RyR channels in the heart and neurons as well as in skeletal muscle.

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“…[11]), and the H1b effect on RyR1 is also consistent with previous results [9,10,14,20,26]. This is the first report of RyR2 activation by H1b or any other Homer isoform.…”

Section: Resultssupporting

confidence: 93%

Section: Resultsmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 98%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 94%

See 3 more Smart Citations

In vitro modulation of the cardiac ryanodine receptor activity by Homer1

Pouliquin

Pace

Dulhunty

2009

Pflugers Arch - Eur J Physiol

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Homer and the ryanodine receptor

Pouliquin

Dulhunty

2009

Eur Biophys J

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Homer proteins have recently been identified as novel high-affinity ligands that modulate ryanodine receptor (RyR) Ca(2+) release channels in heart and skeletal muscle, through an EVH1 domain which binds to proline-rich regions in target proteins. Many Homer proteins can also self-associate through a coiled-coil domain that allows their multimerisation. In other tissues, especially neurons, Homer anchors proteins embedded in the surface membrane to the Ca(2+) release channel in the endoplasmic reticulum and can anchor membrane or cytosolic proteins to the cytoskeleton. Although this anchoring aspect of Homer function has not been extensively investigated in muscle, there are consensus sequences for Homer binding in the RyR and on many of the proteins that it interacts with in the massive RyR ion channel complex. In this review we explore the potential of Homer to contribute to a variety of cell processes in muscle and neurons that also involve RyR channels.

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Novel regulators of RyR Ca2+ release channels: insight into molecular changes in genetically-linked myopathies

Dulhunty¹,

Beard²,

Pouliquin³

et al. 2006

J Muscle Res Cell Motil

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There are many mutations in the ryanodine receptor (RyR) Ca2+ release channel that are implicated in skeletal muscle disorders and cardiac arrhythmias. More than 80 mutations in the skeletal RyR1 have been identified and linked to malignant hyperthermia, central core disease or multi-minicore disease, while more than 40 mutations in the cardiac RyR2 lead to ventricular arrhythmias and sudden cardiac death in patients with structurally normal hearts. These RyR mutations cause diverse changes in RyR activity which either excessively activate or block the channel in a manner that disrupts Ca2+ signalling in the muscle fibres. In a different myopathy, myotonic dystrophy (DM), a juvenile isoform of the skeletal RyR is preferentially expressed in adults. There are two regions of RyR1 that are variably spiced and developmentally regulated (ASI and ASII). The juvenile isoform (ASI(-)) is less active than the adult isoform (ASI(+)) and its over-expression in adults with DM may contribute to functional changes. Finally, mutations in an important regulator of the RyR, the Ca2+ binding protein calsequestrin (CSQ), have been linked to a disruption of Ca2+ homeostasis in cardiac myocytes that results in arrhythmias. We discuss evidence supporting the hypothesis that mutations in each of these situations alter protein/protein interactions within the RyR complex or between the RyR and its associated proteins. The disruption of these protein-protein interactions can lead either to excess Ca2+ release or reduced Ca2+ release and thus to abnormal Ca2+ homeostasis. Much of the evidence for disruption of protein-protein interactions has been provided by the actions of a group of novel RyR regulators, domain peptides with sequences that correspond to sequences within the RyR and which compete with the endogenous residues for their interaction sites.

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Effects of an α-helical ryanodine receptor C-terminal tail peptide on ryanodine receptor activity: Modulation by Homer

Cited by 13 publications

References 43 publications

In vitro modulation of the cardiac ryanodine receptor activity by Homer1

In vitro modulation of the cardiac ryanodine receptor activity by Homer1

Homer and the ryanodine receptor

Novel regulators of RyR Ca2+ release channels: insight into molecular changes in genetically-linked myopathies

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