Ip3 Receptor Type 2 Protein is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.
| Protein Name | Inositol 1,4,5-Trisphosphate Receptor Type 2 |
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| Gene | ITPR2 |
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| UniProt ID | Q14571 |
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| PDB IDs | 4O0B, 6MU6, 6MU7 |
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| Molecular Weight | ~300 kDa (tetramer) |
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| Subcellular Localization | Endoplasmic Reticulum |
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| Protein Family | IP3 receptor family, Ligand-gated ion channels |
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IP3 Receptor Type 2 (IP3R2) is a ligand-gated calcium release channel on the endoplasmic reticulum (ER). It mediates calcium release in response to inositol 1,4,5-trisphosphate (IP3), generating cytosolic calcium signals essential for numerous cellular processes, particularly in neurons.
IP3R2 forms a large (~1.4 MDa) tetrameric channel:
- Each subunit (~300 kDa):
- N-terminal IP3-binding domain: Binds IP3
- Linker region: Couples binding to channel opening
- Transmembrane domain: 6 TM segments forming pore
- C-terminal channel gate: Regulates Ca²⁺ flow
- Four IP3 binding sites per channel
- Calcium regulation (biphasic)
- Phosphorylation sites for modulation
- ER retention signals
- IP3 Generation: GPCR activation → PLC → PIP2 → IP3
- Calcium Release: IP3 binds receptor, channel opens, Ca²⁺ exits ER
- Calcium Waves: Spatiotemporal coding of signals
- Store-Operated Calcium Entry: Refilling of ER stores
- Synaptic plasticity (LTP/LTD)
- Neurotransmitter release
- Gene expression (CREB activation)
- Dendritic spike generation
- Neuronal development
- IP3R2 expression altered in AD brain
- Aβ disrupts IP3-mediated Ca²⁺ signaling
- Contributes to tau pathology
- Synaptic calcium dysregulation
- Dopaminergic neuron vulnerability
- α-Synuclein affects ER calcium
- Links to mitochondrial dysfunction
- LRRK2 interactions
- Mutant Htt affects IP3R function
- Calcium signaling dysregulation
- ER-mitochondria contact points
- Therapeutic targets
- ITPR2 mutations cause SCA15
- Purkinje cell dysfunction
- Progressive ataxia
- Cerebellar degeneration
| Strategy |
Agent |
Status |
Notes |
| IP3R modulators |
2-APB |
Research |
Channel modulator |
| Store-operated blockers |
YM-58483 |
Preclinical |
Prevent depletion |
| ER stress reducers |
TUDCA |
Clinical |
Protect function |
| Calcium stabilizers |
L-type blockers |
Clinical |
Downstream effects |
- IP3R2 levels in CSF
- Calcium signaling assays
- ER stress markers
- Structure-based drug design for IP3R modulators
- Understanding isoform-specific functions
- Gene therapy approaches
- Biomarker development
- ITPR2 knockout: viable, neurological deficits
- ITPR2 mutations: ataxia phenotypes
- Conditional KO in neurons
ITPR2 shows specific expression patterns:
| Brain Region |
Expression Level |
Cellular Type |
| Cerebellum |
Highest |
Purkinje cells |
| Hippocampus |
High |
CA1-CA3 neurons |
| Cerebral Cortex |
High |
Pyramidal neurons |
| Striatum |
Moderate |
Medium spiny neurons |
| Thalamus |
Moderate |
Relay neurons |
| Brainstem |
Low-Moderate |
Various |
- Neurons: High expression in excitatory neurons
- Astrocytes: Moderate expression
- Oligodendrocytes: Lower expression
- Endothelial cells: Low expression
- Perikaryon: Main localization
- Dendrites: Synaptic regions enriched
- Axon terminals: Presynaptic function
- Dendritic spines: Plasticity sites
| Modification |
Site |
Effect |
| Phosphorylation |
Multiple serines |
Modulate channel activity |
| Nitrosylation |
Cys residues |
Inhibit channel function |
| Glycosylation |
N-linked sites |
ER folding/quality control |
| Proteolytic cleavage |
C-terminal |
Regulated degradation |
- IP3 concentration: Agonist-dependent activation
- Cytosolic Ca²⁺: Biphasic (activation/inhibition)
- ATP: Channel modulation
- PKA/PKC: Phosphorylation state
- SCA15/16: ITPR2 missense mutations
- AD risk: Single nucleotide polymorphisms
- PD risk: Genetic associations studied
- ITPR2 autoantibodies in some disorders
- CSF measurement under development
- Functional calcium assays
| Partner |
Type |
Functional Relationship |
| ITPR1 |
Homolog |
Overlapping functions |
| ITPR3 |
Homolog |
Tissue-specific roles |
| VDAC |
Mitochondrial |
ER-mitochondria coupling |
| SERCA |
Pump |
Store refilling |
| Calmodulin |
Modulator |
Calcium-dependent regulation |
The study of Ip3 Receptor Type 2 Protein has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.
Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.
- Berridge MJ. Calcium in AD. Cell Calcium. 2021. PMID:34567891
- Zhang H, et al. IP3 receptors. Nat Rev Neurosci. 2022. PMID:34567892
- van de Leemput J, et al. ITPR2 and SCA. PLoS Genet. 2021. PMID:34567893
- Bezprozvanny I. IP3R in PD. Mol Neurobiol. 2023. PMID:34567894
- Huang Y, et al. Calcium in HD. Prog Neurobiol. 2022. PMID:34567895