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El motivo de unión al dominio de la PDZ regula la expresión y la función del canal NaV1.5 específico del

Diana Shy¹, Ludovic Gillet¹, Jakob Ogrodnik¹

¹From the Department of Clinical Research, University of Bern, Bern, Switzerland (D.S., L.G., J.O., M.A., J.-S.R., M.C.E., N.S., H.A.); Department of Anatomy, Embryology and Physiology (A.O.V.) and Department of Clinical and Experimental Cardiology (R.W., J.B., R.F.M., C.R.B., C.A.R.), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; ICIN-Netherlands Heart Institute, Utrecht, The Netherlands (J.B.); Center for Human and Clinical Genetics, Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands (A.M.v.M.); Institute of Pathology, University of Lausanne, Lausanne, Switzerland (S.R.); Institut National de la Santé et de la Recherche Médicale (INSERM) Unité Mixte de Recherche 1087, L'Institut du Thorax, Nantes, France (R.R.); Centre National de la Recherche Scientifique Unité Mixte de Recherche 6291, Nantes, France (R.R.); Université de Nantes, Nantes, France (R.R.); and Centre Hospitalier Universitaire Nantes, L'Institut du Thorax, Service de Cardiologie, Nantes, France (R.R.).

|June 5, 2014

Resumen

El motivo Ser-Ile-Val (SIV) del canal de sodio cardíaco NaV1.5 es crucial para su expresión en la membrana miocital lateral, impactando la conducción cardíaca. Las mutaciones en este motivo están relacionadas con el síndrome de Brugada, destacando su relevancia clínica.

Área de la Ciencia:

Fisiología cardiovascular fisiología cardiovascular.
Cardiología Molecular Cardiología Molecular
Biología del canal iónico Biología del canal iónico.

Sus antecedentes:

El canal cardíaco de sodio NaV1.5 es esencial para la actividad eléctrica del corazón.
Su motivo C-terminal de unión a la PDZ (Ser-Ile-Val) interactúa con las proteínas de la PDZ, formando complejos funcionales distintos.
El papel preciso in vivo y la importancia clínica de este motivo no estaban claros anteriormente.

Objetivo del estudio:

Investigar el impacto in vivo y clínico del motivo de unión a la PDZ de NaV1.5.
Para aclarar el papel de este motivo en la expresión, función y conducción cardíaca de NaV1.5.

Principales métodos:

Se generaron ratones knock-in que carecen del motivo SIV (ΔSIV).
Se evaluó la expresión de NaV1.5 y la corriente de sodio (INa) utilizando electrofisiología y mapeo óptico.
Investigaron las vías de internalización y degradación de los canales (células HEK293, MG132).
Se examinó a los pacientes para detectar mutaciones dentro del motivo SIV.

Principales resultados:

Los ratones ΔSIV mostraron una reducción de la expresión lateral de NaV1.5 e INa, lo que condujo a un aumento de la anisotropía de conducción ventricular.
El motivo SIV regula la degradación de NaV1.5, como lo demuestra el rescate con un inhibidor del proteasoma.
Un paciente con síndrome de Brugada albergaba una mutación V2016M en el motivo SIV, disminuyendo la expresión de NaV1.5 y INa.

Conclusiones:

El motivo de unión a la PDZ es vital para la localización de NaV1.5 en la membrana lateral de los cardiomiocitos y la conducción ventricular adecuada.
Este motivo juega un papel importante en la regulación de la estabilidad de la proteína NaV1.5.
El motivo SIV tiene relevancia clínica directa en enfermedades cardíacas como el síndrome de Brugada.

Palabras clave:

La distrofina también es conocida como distrofina.canales de sodio de los canales de sodio.La sintropina también se llama sintropina.

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