ITPR1 Membrane Protein Introduction

Introduction of ITPR1

Inositol 1,4,5-trisphosphate receptor type 1 (ITPR1) is a protein that in humans is encoded by the ITPR1 gene. There are three inositol 1,4,5-trisphosphate receptor subtypes in birds and mammals, ITPR1, ITPR2, and ITPR3, and they share basic properties but differ in terms of regulation and distribution. ITPR1 is the dominant subtype in the brain and has been implicated in neuronal development, with higher functions in the central nervous system, and in human neuropathology. A striking feature of ITPRs is the presence of very large cytosolic regions, including the IP3 binding core. The channel domain contains six transmembrane domains, as a result, there are three “loops” that reside in the ER lumen.

Function of ITPR1 Membrane Protein

As an intracellular channel, ITPR1 can mediate calcium release from the endoplasmic reticulum after being stimulated by inositol 1,4,5-trisphosphate. ITPR1 is clustered at the node of Ranvier, in a distribution that is similar to the Nav1.6 sodium channels in the sciatic nerve. ITPR1 is reported to decrease total Ca(2+) signals and terminates Ca(2+) oscillations significantly, playing a predominant role in the function of the vascular smooth muscle. The interaction between ITPR1 and ITPR3 may play a redundant role in the development of the second heart field (SHF). It has been documented that ITPR1 localization, via protein EPB41L1, is necessary for Ca(2+) wave formation, which in turn mediates neurite formation. In addition, ITPR1 regulates the epithelial secretion of electrolytes and promote the fluid through the interaction with AHCYL1. ITPR1 plays a role in ER stress-induced apoptosis.

Fig.1 HIF-2α induces the expression of the autophagy sensor ITPR1 leading to the impairment of NK-mediated renal cell carcinoma killing. (Chouaib, 2018)

Application of ITPR1 Membrane Protein in Literature

1. van de Leemput J., et al. Deletion at ITPR1 underlies ataxia in mice and spinocerebellar ataxia 15 in humans. PLoS Genet. 2007, 3(6): e108. PubMed ID: 17590087
   
   

   The authors conduct heterozygous deletion of the ITPR1 gene, encompassing exons 1-10, 1-40, and 1-44 in those model families, underlies SCA15 in humans.

2. Iwaki A., et al. Heterozygous deletion of ITPR1, but not SUMF1, in spinocerebellar ataxia type 16. J Med Genet. 2008, 45(1): 32-5. PubMed ID: 17932120
   
   

   In this article, the authors detect the copy number of several genes and figure out the deletion of exons 1-48 in ITPR1. They also show the size of the deletion is 318 bp and the telomeric breakpoint is located in the middle of the intergenic region.

3. Hara K., et al. Total deletion and a missense mutation of ITPR1 in Japanese SCA15 families. Neurology. 2008, 71(8): 547-51. PubMed ID: 18579805
   
   

   In this article, they strongly suggest that ITPR1 is the key gene for SCA15 and it is necessary to investigate the point mutation in ITPR1 in the patients with autosomal dominant cerebellar ataxia and tremor.

4. Huang L., et al. Missense mutations in ITPR1 cause autosomal dominant congenital nonprogressive spinocerebellar ataxia. Orphanet J Rare Dis. 2012, 7: 67. PubMed ID: 22986007
   
   

   This article demonstrates that alteration of ITPR1 function can cause a distinct congenital nonprogressive ataxia in addition to spinocerebellar ataxia type 15. It highlights important clinical heterogeneity associated with the ITPR1 gene and a significant role of the ITPR1-related pathway in the development and maintenance of the normal functions of the cerebellum.

5. Schorge S., et al. Human ataxias: a genetic dissection of inositol triphosphate receptor (ITPR1)-dependent signaling. Trends Neurosci. 2010, 33(5): 211-9. PubMed ID: 20226542
   
   

   The article shows that the unifying feature of many genes related to cerebellar ataxias is their impact on ITPR1, which will underlie the coincidence detection in Purkinje cells and plays a vital role in cerebellar coordination.

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Reference

1. Chouaib S, et al. (2018). The role of hypoxia in shaping the recruitment of proangiogenic and immunosuppressive cells in the tumor microenvironment. Contemp Oncol (Pozn). 22(1A): 7-13.

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