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Updated: Jun 24, 2026
Functional Characterization of Endogenously Expressed Human RYR1 Variants
Published on: June 9, 2021
In vitro modulation of the cardiac ryanodine receptor activity by Homer1
Pierre Pouliquin1, Suzy M Pace, Angela F Dulhunty
1Division of Molecular Bioscience, The John Curtin School of Medical Research, The Australian National University, P.O. Box 334, Canberra, ACT 2601, Australia. pierre.pouliquin@anu.edu.au
Insights
Homer1 protein modulates calcium signaling by interacting with ryanodine receptors (RyRs) in the heart and skeletal muscle. This interaction affects RyR channel activity and calcium levels, suggesting Homer1 is an endogenous regulator.
Area of Science:
- Molecular biology
- Cell signaling
- Cardiovascular research
Background:
- Homer proteins regulate calcium signaling complexes, including ryanodine receptors (RyRs).
- Homer1b/c and cardiac RyR2 are co-expressed in the heart and neurons, suggesting potential functional interactions.
- Previous understanding of Homer1b and RyR2 functional interactions was limited.
Purpose of the Study:
- To investigate the functional interaction between Homer1b and RyR2.
- To test the hypothesis that Homer1 regulates both RyR1 and RyR2 isoforms similarly.
- To determine if Homer1's modulation of RyR2 involves ligand binding or multimerization.
Main Methods:
- Single-channel recordings of RyR activity.
- [(3)H]ryanodine binding assays.
- Experiments using full-length Homer1b and a short Homer1 variant.
Main Results:
- Homer1b modulated RyR1 and RyR2 activity, with optimal effects at 50-100 nM.
- Homer1b (50 nM) activated both RyR1 and RyR2 across tested cytosolic calcium concentrations.
- Homer1b reduced the EC(50) for Ca(2+) activation of RyR2, indicating enhanced sensitivity.
- Short Homer1 mimicked Homer1b's effects, suggesting modulation via ligand binding.
Conclusions:
- Homer1b directly modulates the activity of both RyR1 and RyR2.
- Homer1b's action on RyRs is concentration-dependent and occurs via ligand binding.
- Homer1 is a likely endogenous modulator of RyR channels in cardiac, neuronal, and skeletal muscle tissues.
Abstract:
The Homer protein family allows clustering and/or functional modulation of many proteins from different calcium signalling complexes including those formed by the ryanodine receptor (RyR) Ca(2+) release channel in skeletal muscle and the heart. Homer1b/c and the cardiac RyR (RyR2) are strongly expressed in the heart and neurons where their interaction with each other may modulate Ca(2+) signalling. However, functional interactions between Homer1b and RyR2 have been poorly defined. Our preliminary data and similar consensus binding sites for Homer in RyR2 and skeletal RyR (RyR1) proteins, led to the hypothesis that Homer may similarly regulate both RyR isoforms. Single-channel and [(3)H]ryanodine binding data showed that RyR2 and RyR1 activity increased to a maximum with ~50-100 nM Homer1b and fell with Homer1b > 200 nM. Homer1b (50 nM) activated RyR2 and RyR1 at all cytosolic [Ca(2+)]; estimated EC(50) value of RyR2 diminished from ~2.8 microM Ca(2+) (control) to ~1.9 microM Ca(2+) in the presence of 50 nM Homer1b. Short Homer1 (lacking the coiled-coil multimerisation domain) and Homer1b similarly modulated RyR2, indicating an action through ligand binding, not mutimerisation. These actions of Homer were generally similar in RyR2 and RyR1. The strong functional interactions suggest that Homer1 is likely to be an endogenous modulator of RyR channels in the heart and neurons as well as in skeletal muscle.
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