| IP₃ Receptor (ITPR1) | |
|---|---|
| Gene | [ITPR1](/genes/itpr1) |
| UniProt ID | [Q14643](https://www.uniprot.org/uniprot/Q14643) |
| PDB | 6MU2, 6MU3, 7L9Z, 8EAR |
| Molecular Weight | 314 kDa (monomer), ~1.2 MDa tetramer |
| Localization | Endoplasmic reticulum membrane |
| Family | Intracellular calcium release channel family |
| Disease | SCA15/16, SCA29, AD, ALS |
The inositol 1,4,5-trisphosphate receptor (IP₃R) is a large calcium release channel located on the endoplasmic reticulum (ER) membrane. IP₃Rs mediate calcium release from ER stores in response to IP₃ generated by phospholipase C activation. IP₃R dysfunction contributes to calcium dyshomeostasis in Alzheimer's disease, ALS, and spinocerebellar ataxias.
IP₃R is a massive tetrameric channel (~1.2 MDa) with each subunit containing:
Each subunit contributes one pore-forming region. The channel opens when IP₃ binds to the N-terminal domains on all four subunits[1].
IP₃Rs have critical roles in calcium signaling:
Three IP₃R isoforms exist with distinct properties:
IP₃R dysfunction contributes to AD pathogenesis[2]:
Mechanisms of enhanced IP₃R signaling in AD:
ITPR1 mutations cause several cerebellar ataxias:
SCA15/16: Deletions and missense mutations
SCA29: Missense mutations
IP₃R involvement in motor neuron disease:
| Strategy | Mechanism | Status |
|---|---|---|
| 2-APB | IP₃R inhibitor (non-specific) | Research tool |
| Xestospongin C | IP₃R inhibitor | Research tool |
| Dantrolene | RyR inhibitor (cross-reactivity) | Clinical (malignant hyperthermia) |
| Calcium stabilizers | Reduce ER-mito transfer | Preclinical |
| Dantrolene derivatives | Improved specificity | Preclinical |
Fan et al. Structure of the IP3 receptor. 2018. ↩︎
Leissring et al. Presenilin-mediated IP₃R modulation in AD. J Neurosci. 2001. ↩︎
Iwaki et al. ITPR1 mutations in SCA29. Am J Hum Genet. 2008. ↩︎