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A mechanism of ryanodine receptor modulation by FKBP12/12.6, protein kinase A, and K201

Blayney, Lynda Mary, Jones, Jonathan-Lee, Griffiths, Julia and Lai, Francis Anthony 2009. A mechanism of ryanodine receptor modulation by FKBP12/12.6, protein kinase A, and K201. Cardiovascular Research 85 (1) , pp. 68-78. 10.1093/cvr/cvp273

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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 Ca2+ concentration was used to modulate the open/closed conformation of RyR1/2 channels measured using [3H]ryanodine binding assays. The affinity constant—KA, 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 KA of the closed conformation by increasing the rate of dissociation kd. K201 reduced [3H]ryanodine binding to RyR1/2 at all free Ca2+ 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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Subjects: R Medicine > R Medicine (General)
Uncontrolled Keywords: Ryanodine receptor; FKBP12/12.6; Protein kinase A phosphorylation; Arrhythmia (mechanisms; K201
Publisher: Elsevier
ISSN: 0008-6363
Last Modified: 07 Apr 2020 13:25
URI: http://orca.cf.ac.uk/id/eprint/26831

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