# Natural Agonists of Ryanodine Receptors: Structure-function Relationship and Antiarrhythmic Properties

> **NIH NIH R01** · UNIVERSITY OF WISCONSIN-MADISON · 2020 · $463,224

## Abstract

ABSTRACT
 Ryanodine receptors (RyR) are sarcoplasmic reticulum Ca2+ release channels that play a critical role in
Ca2+ signaling of excitable and non-excitable cells. RyRs owe their name to the fact that they were characterized in
great part thanks to ryanodine, a plant alkaloid that binds to RyRs with high affinity and specificity. Ryanodine has
been an invaluable ligand of RyRs, but its functional effects are complex and hamper its use in cellular studies. In
search of novel ligands that could overcome some of the functional and structural disadvantages of ryanodine, we
found in the venom of selected scorpions a set of peptide ligands, termed calcins, displaying high affinity and
exquisite selectivity against RyRs. The defining characteristic of calcins is their capacity to stabilize RyR openings in
a long-lasting subconducting state. This effect is nearly analogous to that of ryanodine, but unlike ryanodine, calcins
bind rapidly to RyRs (fast association rate), freely dissociate from their binding site (reversible effect), display a dose-
and sequence-variable effect, and are amenable for derivatization without undergoing major loss in receptor affinity.
Calcins also modulate intracellular Ca2+ in intact cardiomyocytes with remarkable speed and with several degrees of
potency, thus entering the field as the first cell-penetrating peptides (CPP) RyR-specific Ca2+ mobilizer of high
dynamic range. This research program will characterize first and then exploit this novel group of peptide ligands to
unravel fundamental mechanisms of RyR function at the molecular, cellular and whole heart level. Our multidisciplinary
program, with well-defined deliverables and milestones, may be enveloped in two specific aims. In the first aim, we
will first identify and modify the structural domains of calcins involved in RyR recognition and cell penetration to
generate a group of functionally diverse CPPs capable of modulating RyR function with wide dynamic range and of
delivering cargo to the interior of cardiomyocytes. In the second aim, we will use native and mutant calcins on intact
cardiomyocytes, Langendorff-perfused working hearts and intact animals to create acute or sustained periods of RyR
hyperactivity and reveal mechanisms of RyR gating, SR Ca2+ load and Ca2+-triggered arrhythmias. These studies use
animal models of catecholaminergic polymorphic ventricular tachycardia to develop a novel paradigm for the treatment
of calcium-dependent arrhythmias; results may be applied to other cardiomyopathies where controlled unloading of
SR Ca2+ may be desirable.

## Key facts

- **NIH application ID:** 9905552
- **Project number:** 5R01HL134344-04
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Hector H Valdivia
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $463,224
- **Award type:** 5
- **Project period:** 2017-04-01 → 2021-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9905552

## Citation

> US National Institutes of Health, RePORTER application 9905552, Natural Agonists of Ryanodine Receptors: Structure-function Relationship and Antiarrhythmic Properties (5R01HL134344-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9905552. Licensed CC0.

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