ITPR1

ITPR1 Background

The ITPR1 gene encodes inositol 1,4,5-trisphosphate receptor type 1 (IP3R1), a ligand-gated ion channel that mediates calcium release from the endoplasmic reticulum ^[1]. Like the other two IP3Rs, IP3R1 is a tetramer, with each subunit encompassing an N-terminus, six transmembrane domains, and a C-terminal tail ^[2][3]. The N-terminus contains an inositol 1,4,5-trisphosphate (IP3)-binding domain, a suppressor domain that inhibits IP3 binding, and a regulatory domain ^[4]. This regulatory domain contains binding sites for Ca2⁺ and ATP as well as consensus phosphorylation sites ^[2][5][6]. The transmembrane and C-terminal domains are essential for the tetramerization of IP3Rs ^[7][8]. ITPR1/IP3R1 is widely expressed in the central nervous system and particularly in the cerebellar Purkinje cells ^[9]. IP3, a catalytic cleavage product of the phospholipid phosphatidylinositol 4,5-bisphosphate (PIP2), binds to the IP3R1, redistributing Ca2⁺ from the ER to cytosol, which causes an increase in the cytosolic Ca2⁺ concentration ^[10]. Elevated Ca2⁺ levels further activate Ca2⁺-dependent proteins, inducing a cascade of intracellular responses, including cell division, cell proliferation, apoptosis, fertilization, development, behavior, memory, and learning ^[11]. Assefa Z et al. confirmed that IP3R1 plays a pivotal role in apoptosis and that the increase in Ca2⁺ concentration during apoptosis is mainly the consequence of IP3R1 cleavage by caspase-3 ^[12]. The IP3R1-mediated Ca2⁺ release also plays a crucial role in synaptic gene expression, development, and neuromuscular transmission, as well as mediating degeneration during excessive cholinergic activation ^[13]. Silencing of IP3R1 prevented apoptosis induction in colorectal cancer DLD1 cells, ovarian cancer A2780cells, and clear cell renal cell carcinoma RCC4 cells, compared to apoptosis in cells treated with scrambled siRNA. Previous experiments have shown that most IP3R1 knock-out (KO) mice did not survive the period of prenatal development ^[14]. Deletions of ITPR1 are known to cause spinocerebellar ataxia type 15, a distinct and very slowly progressive form of cerebellar ataxia with onset in adulthood ^[15]. Gerber S. et al. demonstrated that biallelic and monoallelic ITPR1 mutations as the underlying genetic defects for Gillespie syndrome (GS), a rare variant form of aniridia characterized by non-progressive cerebellar ataxia, intellectual disability, and iris hypoplasia ^[16].

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[12] Assefa Z, Bultynck G, et al. Caspase-3-induced truncation of type 1 inositol trisphosphate receptor accelerates apoptotic cell death and induces inositol trisphosphate-independent calcium release during apoptosis [J]. J Biol Chem. 2004 Oct 8;279(41):43227-36.
[13] Zhu H, Bhattacharyya BJ, et al. Skeletal muscle IP3R1 receptors amplify physiological and pathological synaptic calcium signals [J]. J Neurosci. 2011 Oct 26;31(43):15269-8.
[14] Matsumoto M, Nakagawa T, et al. Ataxia and epileptic seizures in mice lacking type 1 inositol 1,4,5-trisphosphate receptor [J]. Nature 1996, 379, 168-171.
[15] van de Leemput J, Chandran J, et al. Deletion at ITPR1 underlies ataxia in mice and spinocerebellar ataxia 15 in humans [J]. PLoS Genetics. 2007, 3 (6): e108.
[16] Gerber S., Alzayady K.J., et al. Recessive and dominant de novo ITPR1 mutations cause Gillespie syndrome [J]. Am. J. Hum. Genet. 2016, 98:971-980.