Ryanodine receptor 2 (RyR2) (encoded by the RYR2 gene) is the predominant intracellular calcium release channel in cardiac muscle and is highly expressed throughout the brain. In 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.
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 neurons, cortical pyramidal cells, and other neuronal populations[2]. Neuronal RyR2-mediated CICR amplifies calcium signals from voltage-gated channels and NMDA receptors, modulating synaptic plasticity, gene expression, and neuronal excitability. [1]
| Protein Name | Ryanodine Receptor 2 (RyR2) |
| Gene | RYR2 |
| UniProt ID | 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 |
RyR2 is the primary mediator of CICR in neurons[2]:
Unlike skeletal muscle RyR1, which is mechanically gated by Cav1.1, neuronal/cardiac RyR2 is activated by Ca²⁺ itself (CICR) and modulated by:
RyR2 is critically involved in AD calcium dysregulation[3]:
| 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 |
Bhatt DG et al. Ryanodine receptors in neuronal physiology and disease (2014). 2014. ↩︎