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Dries, E; Bito, V; Lenaerts, I; Antoons, G; Sipido, KR; Macquaide, N.
Selective modulation of coupled ryanodine receptors during microdomain activation of calcium/calmodulin-dependent kinase II in the dyadic cleft.
Circ Res. 2013; 113(11):1242-1252 Doi: 10.1161/CIRCRESAHA.113.301896 [OPEN ACCESS]
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Antoons Gudrun

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Rationale: In ventricular myocytes of large mammals with low T-tubule density, a significant number of ryanodine receptors (RyRs) are not coupled to the sarcolemma; cardiac remodeling increases noncoupled RyRs. Objective: Our aim was to test the hypothesis that coupled and noncoupled RyRs have distinct microdomain-dependent modulation. Methods and Results: We studied single myocytes from pig left ventricle. The T-tubule network was analyzed in 3-dimension (3D) to measure distance to membrane of release sites. The rising phase of the Ca2+ transient was correlated with proximity to the membrane (confocal imaging, whole-cell voltage-clamp, K(5)fluo-4 as Ca2+ indicator). Ca2+ sparks after stimulation were thus identified as resulting from coupled or noncoupled RyRs. We used high-frequency stimulation as a known activator of Ca2+/calmodulin-dependent kinase II. Spark frequency increased significantly more in coupled than in noncoupled RyRs. This specific modulation of coupled RyRs was abolished by the Ca2+/calmodulin-dependent kinase II blockers autocamtide-2-related inhibitory peptide and KN-93, but not by KN-92. Colocalization of Ca2+/calmodulin-dependent kinase II and RyR was not detectably different for coupled and noncoupled sites, but the F-actin disruptor cytochalasin D prevented the specific modulation of coupled RyRs. NADPH oxidase 2 inhibition by diphenyleneiodonium or apocynin, or global reactive oxygen species scavenging, also prevented coupled RyR modulation. During stimulated Ca2+ transients, frequency-dependent increase of the rate of Ca2+ rise was seen in coupled RyR regions only and abolished by autocamtide-2-related inhibitory peptide. After myocardial infarction, selective modulation of coupled RyR was lost. Conclusions: Coupled RyRs have a distinct modulation by Ca2+/calmodulin-dependent kinase II and reactive oxygen species, dependent on an intact cytoskeleton and consistent with a local Ca2+/reactive oxygen species microdomain, and subject to modification with disease.
Find related publications in this database (using NLM MeSH Indexing)
Animals -
Calcium - metabolism
Calcium-Calmodulin-Dependent Protein Kinase Type 2 - physiology
Disease Models, Animal -
Imaging, Three-Dimensional -
Membrane Microdomains - physiology
Microscopy, Confocal -
Myocardial Infarction - metabolism Myocardial Infarction - pathology Myocardial Infarction - physiopathology
Myocytes, Cardiac - pathology Myocytes, Cardiac - physiology
Patch-Clamp Techniques -
Reactive Oxygen Species - metabolism
Ryanodine Receptor Calcium Release Channel - physiology
Sarcolemma - physiology
Sarcoplasmic Reticulum - metabolism
Swine -

Find related publications in this database (Keywords)
calcium/calmodulin-dependent protein kinase type 2
myocytes, cardiac
NADPH oxidase
reactive oxygen species
ryanodine receptor calcium release channel
sarcoplasmic reticulum
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