Ryanodine Receptor 2 (RyR2 Protein)

Ryanodine Receptor 2 (RyR2 Protein)

Introduction

Ryanodine receptor 2 (RyR2) (encoded by the [RYR2 gene](/genes/ryr2)) is the predominant intracellular calcium release channel in cardiac muscle and is highly expressed throughout the brain. In [neurons](/entities/neurons), RyR2 is the major mediator of calcium-induced calcium release (CICR) and plays critical roles in synaptic plasticity, learning, and memory — processes disrupted in neurodegenerative diseases.

Overview

RyR2 is a homotetrameric calcium release channel of ~2.2 MDa located in the endoplasmic reticulum (ER) membrane^[1]. Each subunit is 4,967 amino acids. RyR2 is the predominant ryanodine receptor isoform in the brain, expressed in [hippocampal](/brain-regions/hippocampus) neurons, [cortical](/brain-regions/cerebral-cortex) pyramidal cells, and other neuronal populations^[2]. Neuronal RyR2-mediated CICR amplifies calcium signals from voltage-gated channels and [NMDA receptors](/proteins/grin1-protein), modulating synaptic plasticity, gene expression, and neuronal excitability. [@bhatt2014]

<div class="infobox infobox-protein"> [@bhatt2017]

| | |
|---|---|
| Protein Name | Ryanodine Receptor 2 (RyR2) |
| Gene | [RYR2](/genes/ryr2) |
| UniProt ID | [Q92736](https://www.uniprot.org/uniprot/Q92736) |
| Molecular Weight | ~565 kDa (monomer), ~2.2 MDa (tetramer) |
| Length | 4,967 amino acids |
| Subcellular Localization | ER/SR membrane |
| Function | Intracellular Ca²⁺ release channel; CICR |

</div>

Function

Neuronal Calcium Signaling

Ryanodine Receptor 2 (RyR2 Protein)

Introduction

Ryanodine receptor 2 (RyR2) (encoded by the [RYR2 gene](/genes/ryr2)) is the predominant intracellular calcium release channel in cardiac muscle and is highly expressed throughout the brain. In [neurons](/entities/neurons), RyR2 is the major mediator of calcium-induced calcium release (CICR) and plays critical roles in synaptic plasticity, learning, and memory — processes disrupted in neurodegenerative diseases.

Overview

RyR2 is a homotetrameric calcium release channel of ~2.2 MDa located in the endoplasmic reticulum (ER) membrane^[1]. Each subunit is 4,967 amino acids. RyR2 is the predominant ryanodine receptor isoform in the brain, expressed in [hippocampal](/brain-regions/hippocampus) neurons, [cortical](/brain-regions/cerebral-cortex) pyramidal cells, and other neuronal populations^[2]. Neuronal RyR2-mediated CICR amplifies calcium signals from voltage-gated channels and [NMDA receptors](/proteins/grin1-protein), modulating synaptic plasticity, gene expression, and neuronal excitability. [@bhatt2014]

<div class="infobox infobox-protein"> [@bhatt2017]

| | |
|---|---|
| Protein Name | Ryanodine Receptor 2 (RyR2) |
| Gene | [RYR2](/genes/ryr2) |
| UniProt ID | [Q92736](https://www.uniprot.org/uniprot/Q92736) |
| Molecular Weight | ~565 kDa (monomer), ~2.2 MDa (tetramer) |
| Length | 4,967 amino acids |
| Subcellular Localization | ER/SR membrane |
| Function | Intracellular Ca²⁺ release channel; CICR |

</div>

Function

Neuronal Calcium Signaling

RyR2 is the primary mediator of CICR in neurons^[2]:

• CICR amplification: Small Ca²⁺ influx through NMDA receptors or voltage-gated Ca²⁺ channels triggers RyR2 opening, amplifying the signal
• Synaptic plasticity: Essential for [long-term potentiation](/mechanisms/long-term-potentiation) (LTP) and long-term depression (LTD) in [hippocampus](/brain-regions/hippocampus)
• Dendritic Ca²⁺ waves: RyR2-mediated calcium waves propagate along dendrites, influencing synaptic integration
• Presynaptic release: Enhances neurotransmitter vesicle fusion through presynaptic Ca²⁺ amplification
• Nuclear Ca²⁺ signaling: ER-nuclear envelope continuity allows RyR2-mediated Ca²⁺ to activate nuclear CREB and gene transcription

Key Difference from RyR1

Unlike skeletal muscle [RyR1](/proteins/ryr1-protein), which is mechanically gated by Cav1.1, neuronal/cardiac RyR2 is activated by Ca²⁺ itself (CICR) and modulated by:

• Ca²⁺: Low cytoplasmic Ca²⁺ activates; high Ca²⁺ inhibits (bell-shaped response)
• Caffeine: Pharmacological activator (lowers Ca²⁺ threshold for opening)
• cAMP/PKA: Phosphorylation at Ser2808 increases open probability
• CaMKII: Phosphorylation at Ser2814 modulates channel activity

Role in Neurodegeneration

Alzheimer's Disease

RyR2 is critically involved in AD calcium dysregulation^[3]:

• Presenilin-mediated ER Ca²⁺ leak: [PSEN1](/genes/psen1)/[PSEN2](/genes/psen2) mutations cause excessive RyR2-mediated Ca²⁺ release
• [Aβ](/proteins/amyloid-beta)-induced CICR: [Amyloid-β](/proteins/amyloid-beta-protein) oligomers sensitize RyR2 to Ca²⁺, amplifying excitotoxic signals
• RyR2 upregulation: RyR2 expression is increased in AD brain and mouse models
• Synaptic failure: Excessive ER Ca²⁺ release disrupts synaptic plasticity → cognitive decline
• Calstabin2 dissociation: Oxidative stress and PKA hyperphosphorylation cause FKBP12.6 (calstabin2) loss → leaky channels

Parkinson's Disease

• Dopaminergic neuron vulnerability: RyR2-mediated Ca²⁺ contributes to calcium burden in [substantia nigra](/brain-regions/substantia-nigra) neurons
• [α-Synuclein](/proteins/alpha-synuclein): May sensitize RyR2 channels to Ca²⁺

Therapeutic Targeting

• Dantrolene: RyR antagonist; reduces ER Ca²⁺ leak; showed benefit in AD mouse models
• Rycal compounds (S107, ARM210): Stabilize FKBP12.6 binding to RyR2, reducing pathological leak without blocking physiological Ca²⁺ release
• JTV-519: Stabilizes calstabin-RyR2 interaction

Protein Interactions

| Interactor | Type | Function |
|-----------|------|----------|
| FKBP12.6 (Calstabin-2) | Stabilizer | Stabilizes closed state; dissociation → pathological Ca²⁺ leak |
| Calmodulin | Modulator | Ca²⁺-dependent modulation |
| PKA | Kinase | Phosphorylates Ser2808; β-adrenergic regulation |
| CaMKII | Kinase | Phosphorylates Ser2814 |
| PP1/PP2A | Phosphatases | Dephosphorylate RyR2; restore basal activity |
| Sorcin | Modulator | Ca²⁺-dependent RyR2 inhibitor |

See Also

• [RYR2 Gene](/genes/ryr2)
• [RyR1 Protein](/proteins/ryr1-protein)
• [RyR3 Protein](/proteins/ryr3-protein)
• [Calcium Dysregulation in Neurodegeneration](/mechanisms/calcium-dysregulation-neurodegeneration)
• [PSEN1 Gene](/genes/psen1)

External Links

• [RyR2 - UniProt](https://www.uniprot.org/uniprot/Q92736)
• [RYR2 - NCBI Gene](https://www.ncbi.nlm.nih.gov/gene/6262)

References