A protein-degradation mechanism opens a new treatment route for an inherited arrhythmia

· Medical Xpress

by Centro Nacional de Investigaciones Cardiovasculares

edited by Gaby Clark, reviewed by Andrew Zinin

Gaby Clark

Scientific Editor

Meet our editorial team
Behind our editorial process

Andrew Zinin

Chief Editor

Meet our editorial team
Behind our editorial process Editors' notes

This article has been reviewed according to Science X's editorial process and policies. Editors have highlighted the following attributes while ensuring the content's credibility:

fact-checked

peer-reviewed publication

trusted source

proofread

The GIST Add as preferred source

The R33Q mutation in calsequestrin 2 (CASQ2) disrupts calcium control in heart cells and activates protein-degradation mechanisms. Credit: CNIC

An international team has identified a protein-degradation mechanism that contributes to the development of an inherited form of catecholaminergic polymorphic ventricular tachycardia (CPVT), a disease that mainly affects children and young people. The study was led by researchers at the Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), in collaboration with the University of Pavia and IRCCS Istituti Clinici Scientifici Maugeri in Italy.

The study, published in the journal Circulation Research, also identifies a possible therapeutic strategy based on inhibiting the enzyme calpain. Researchers from the Spanish cardiovascular research network (CIBERCV) also took part in the study.

CPVT is a life-threatening inherited arrhythmic disease that can cause loss of consciousness and even sudden death, mainly in children and young adults. A particularly dangerous feature of the disease is that arrhythmias often appear during exercise or emotional stress, when the heart's activity increases.

The study, led by Dr. Enrique Lara-Pezzi, head of the Molecular Regulation of Heart Failure group at the CNIC, in collaboration with Dr. Silvia G. Priori of IRCCS Istituti Clinici Scientifici Maugeri and the University of Pavia, examined a form of CPVT caused by a mutation in the gene encoding calsequestrin, a protein that helps control calcium inside heart cells. Calcium is essential for the heart to contract in a coordinated way with every beat, and disruptions to its regulation can trigger abnormal heart rhythms.

Calpain inhibition reduces ventricular arrhythmias. Representative ECG recordings from mice with CPVT, untreated or treated with a calpain inhibitor, after administration of adrenaline to trigger arrhythmias (left). Treatment reduced the proportion of animals that developed sustained ventricular tachycardia (right). Credit: CNIC

Using a combination of proteomics techniques, experimental models, and cellular and biochemical studies, the team discovered that the problem does not end with the initial disruption of calcium handling. This abnormality, explains Lara-Pezzi, "activates various cellular degradation mechanisms that reduce the levels of essential proteins in the molecular complex responsible for regulating calcium release inside cardiomyocytes."

One of the standout mechanisms involves the calcium-dependent enzyme calpain. The team showed that calpain activity is increased in animals with the mutation and directly targets triadin (TRDN), a protein that helps stabilize the calcium-release machinery.

The results also reveal a previously unknown sequence of events: Degradation of triadin precedes the loss of mutant calsequestrin and contributes to its destabilization.

The researchers emphasize that pharmacological blockade of calpain restored several proteins of this machinery, improved calcium handling in heart cells and reduced the occurrence of ventricular arrhythmias in mice with the disease.

"Our results identify protein degradation as an important mechanism contributing to the development of this form of CPVT, and show that calpain could represent a new therapeutic target," says CNIC researcher Dr. Laura Ramos-Hernández, first author of the study.

The authors nevertheless stress that these are preclinical results. Further studies are needed to determine whether this calpain-mediated degradation mechanism is also present in other forms of CPVT and in other cardiac diseases before considering its possible use in clinical practice.

Publication details

Laura Ramos-Hernández et al, Calpain-Dependent Protein Degradation Contributes to CASQ2-R33Q CPVT, Circulation Research (2026). DOI: 10.1161/circresaha.126.329035

Journal information: Circulation Research

Key medical concepts

Catecholaminergic polymorphic ventricular tachycardiaVentricular Arrhythmia

Clinical categories

Cardiology Provided by Centro Nacional de Investigaciones Cardiovasculares Who's behind this story?

Gaby Clark

MA in English, copy editor since 2021 with experience in higher education and health content. Dedicated to trustworthy science news. Full profile →

Andrew Zinin

Master's in physics with research experience. Long-time science news enthusiast. Plays key role in Science X's editorial success. Full profile →

Citation: A protein-degradation mechanism opens a new treatment route for an inherited arrhythmia (2026, September 26) retrieved 26 September 2026 from https://medicalxpress.com/news/2026-09-protein-degradation-mechanism-treatment-route.html This document is subject to copyright. Apart from any fair dealing for the purpose of private study or research, no part may be reproduced without the written permission. The content is provided for information purposes only.