Physiological consequences of the P2328S mutation in the ryanodine receptor (RyR2) gene in genetically modified murine hearts.

Goddard, C A; Ghais, N S; Zhang, Y; Williams, A J; Colledge, W H; Grace, A A; Huang, C L-H

Goddard, C A; Ghais, N S; Zhang, Y; Williams, A J; Colledge, W H; Grace, A A; Huang, C L-H.

Afiliación

Goddard CA; Physiological Laboratory, University of Cambridge, Cambridge, UK.

Acta Physiol (Oxf) ; 194(2): 123-40, 2008 Oct.

Article en En | MEDLINE | ID: mdl-18419777

RESUMEN

AIM: To explore the physiological consequences of the ryanodine receptor (RyR2)-P2328S mutation associated with catecholaminergic polymorphic ventricular tachycardia (CPVT). METHODS: We generated heterozygotic (RyR2 p/s) and homozygotic (RyR2 s/s) transgenic mice and studied Ca2+ signals from regularly stimulated, Fluo-3-loaded, cardiac myocytes. Results were compared with monophasic action potentials (MAPs) in Langendorff-perfused hearts under both regular and programmed electrical stimulation (PES). RESULTS: Evoked Ca2+ transients from wild-type (WT), heterozygote (RyR2 p/s) and homozygote (RyR2 s/s) myocytes had indistinguishable peak amplitudes with RyR2 s/s showing subsidiary events. Adding 100 nm isoproterenol produced both ectopic peaks and subsidiary events in WT but not RyR2 p/s and ectopic peaks and reduced amplitudes of evoked peaks in RyR2 s/s. Regularly stimulated WT, RyR2 p/s and RyR2 s/s hearts showed indistinguishable MAP durations and refractory periods. RyR2 p/s hearts showed non-sustained ventricular tachycardias (nsVTs) only with PES. Both nsVTs and sustained VTs (sVTs) occurred with regular stimuli and PES with isoproterenol treatment. RyR2 s/s hearts showed higher incidences of nsVTs before but mainly sVTs after introduction of isoproterenol with both regular stimuli and PES, particularly at higher pacing frequencies. Additionally, intrinsically beating RyR2 s/s showed extrasystolic events often followed by spontaneous sVT. CONCLUSION: The RyR2-P2328S mutation results in marked alterations in cellular Ca2+ homeostasis and arrhythmogenic properties resembling CPVT with greater effects in the homozygote than the heterozygote demonstrating an important gene dosage effect.

Asunto(s)

Mutación; Miocitos Cardíacos/metabolismo; Canal Liberador de Calcio Receptor de Rianodina/genética; Taquicardia Ventricular/genética; Potenciales de Acción; Animales; Calcio/metabolismo; Estimulación Cardíaca Artificial/métodos; Células Cultivadas; Heterocigoto; Homeostasis; Homocigoto; Ratones; Ratones Transgénicos; Técnicas de Cultivo de Órganos; Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos; Canal Liberador de Calcio Receptor de Rianodina/fisiología; Taquicardia Ventricular/metabolismo

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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Taquicardia Ventricular / Canal Liberador de Calcio Receptor de Rianodina / Miocitos Cardíacos / Mutación Límite: Animals Idioma: En Revista: Acta Physiol (Oxf) Asunto de la revista: FISIOLOGIA Año: 2008 Tipo del documento: Article Pais de publicación: Reino Unido

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