# Ryanodine receptor structure and function in heart failure

> **NIH NIH P01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2024 · $419,146

## Abstract

Project Summary
The overarching goal of this PPG is to define the molecular mechanisms that regulate local calcium (Ca2+)
signaling in normal and failing hearts with unprecedented precision. There are three goals shared by the four
projects: 1) explore the precise role of adrenergic signaling in modulating calcium in normal and failing hearts;
2) define novel mechanisms of interactions between T-tubule and sarcoplasmic reticulum (SR) calcium channels;
3) develop new understandings of genetic based mechanisms of inherited forms of CV disease involving calcium.
Project four provides the essential link to SR calcium release by studying the structure-function relationships of
the type 2 ryanodine receptor (RyR2)/calcium release channel present on the sarcoplasmic and endoplasmic
reticula (SR/ER) of many cell types in the context of heart failure (chronic HF with reduced ejection fraction,
HFrEF). RyR2 channels are required for Ca2+ release from intracellular stores that triggers excitation-contraction
(EC) coupling in the cardiac muscle. Inherited RyR2 mutations can cause arrhythmias including exercise-induced
sudden death or catecholaminergic polymorphic ventricular tachycardia (CPVT), and stress-induced post-
translational modifications of RyR2 contribute to heart failure (HF) progression. In both cases RyR2 channels
are leaky either due to inherited mutations (CPVT) or acquired post-translational modifications (HF). Unanswered
questions include: 1) can (and if so how) RyR2 mutations can cause HF; 2) what is the precise mechanism by
which PKA phosphorylation activates RyR2 and plays a role in HF? Preliminary data using cryo-EM to solve the
structure of human RyR2 at ~2.4 Å show that a human CPVT mutation RyR2-R2474S puts the channel into a
“primed state” from which it can be readily and pathologically activated at low, normally non-activating [Ca2+]cyt
explaining why these channels are leaky and cause fatal ventricular arrhythmias during exercise or stress. The
Rycal drug ARM210 binds to RyR2 and restores the mutant channel back to a stable closed state preventing
leak and arrhythmias. The applicant hypothesizes that RyR2 missense mutations, 14 of which are found in
patients with a ClinVar prediction of cardiomyopathy in patients from the Pakistan Genome Resource (PGR), a
unique cohort of individuals with extensive phenotype data and high rates of consanguinity, (Core A), may be
gain of function (GoF) mutations that also put the channel into a primed state which is even more sensitive to
activation compared to the CPVT mutations. Thus, these patients have leaky RyR2 channels and develop HF
due to depletion of SR Ca2+ resulting in impaired cardiac contractility. These questions will be addressed using
functional and structural assays and using a novel drug, Rycal (ARM210), that fixes the RyR2 mediated SR
Ca2+ leak via a well-defined mechanism. Three aims are proposed: 1) Evaluate changes in the function and
structure of RyR2 GoF missense variants li...

## Key facts

- **NIH application ID:** 10839859
- **Project number:** 5P01HL164319-02
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** ANDREW Robert MARKS
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $419,146
- **Award type:** 5
- **Project period:** 2023-05-15 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10839859

## Citation

> US National Institutes of Health, RePORTER application 10839859, Ryanodine receptor structure and function in heart failure (5P01HL164319-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10839859. Licensed CC0.

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