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FLASH GENE

Symbol

ITPR1

contributors: mct/npt - updated : 25-05-2016

HGNC name	inositol 1,4,5-triphosphate receptor, type 1
HGNC id	6180

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

Corresponding disease	CLA4 cerebellar ataxia 4 GLSPS2 Gillespie syndrome 2 SCA15 spinocerebellar ataxia 15 SCA16 spinocerebellar ataxia 16
Location	3p26.1      Physical location : 4.535.031 - 4.889.522
Synonym name	IP3 receptor isoform 1
	type 1 inositol 1,4,5-trisphosphate receptor
Synonym symbol(s)	IP3R1, INSP3R1, IP3R, DKFZp313N1434, DKFZp313E1334, ACV, CLA4, INSP3R1, PPP1R94,

DNA

TYPE	functioning gene
STRUCTURE	354.49 kb     59 Exon(s)

10 Kb 5' upstream gene genomic sequence study

MAPPING

cloned

Y

linked

N

status

provisional

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_001099952 59 - 10098 NP_001093422 - 2710 - 2016 27108797 NM_002222 58 - 10053 NP_002213 - 2695 - 2016 27108797 lacks exon 12 NM_001168272 61 - 10197 NP_001161744 - 2743 - 2016 27108797 lacks exon 12, uses an alternate in-frame splice site in intron 23, and includes three additional exons between variant 1 exons 39 and 40

EXPRESSION

Type

widely

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Cardiovascular heart       moderately Nervous brain       predominantly Homo sapiens Reproductive male system prostate     highly Respiratory lung       moderately Urinary kidney       highly

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Blood / Hematopoietic bone marrow       Connective bone       Nervous peripherous     highly Homo sapiens

cells

System Cell Pubmed Species Stage Rna symbol Blood/Hematopoietic platelet Nervous neuron Homo sapiens Nervous Purkinje cell Homo sapiens

cell lineage

cell lines

fluid/secretion

at STAGE

PROTEIN

PHYSICAL PROPERTIES		Hydrophilic
STRUCTURE

motifs/domains	a N terminal cytoplasmic ligand binding domain linked by a modulatory domain to a channel forming hydrophobic domain made of six membrane-spanning segments near the C terminus (calcium channel)
	ATP binding sites (GXGXXG sequence)
	a IRBIT (inositol triphosphate receptor binding protein) domain
	a central transducing/modulatory domain,
	a C-terminal channel domain

conjugated

ubiquitinated

mono polymer

homomer , tetramer

HOMOLOGY

Homologene

FAMILY

INSP3 receptor family

CATEGORY

receptor membrane

SUBCELLULAR LOCALIZATION	intracellular
	intracellular,cytoplasm,organelle,membrane
	intracellular,cytoplasm,organelle,endoplasmic reticulum
	intracellular,nucleus,nucleolus
text	intracellular membranes of platelets
	coexpressed with RYR3
	clustered at the node of Ranvier, in a distribution that is similar to the Nav1.6 sodium channels in the sciatic nerve

basic FUNCTION	inositol 1,4,5-triphosphate receptor, involved in Ca++ mobilization from the endoplastic reticulum
	major neuronal member in the central nervous system
	significantly decreases total Ca(2+) signals and terminates Ca(2+) oscillations
	playing a predominant role in the function of the vascular smooth muscle
	ITPR1 and ITPR3 may play a redundant role in the development of the second heart field (SHF)
	ITPR1 localization, via protein EPB41L1, is necessary for Ca(2+) wave formation, which in turn mediates neurite formation
	role for the HIF2A/ITPR1 axis in regulating Clear cell renal carcinomas cell survival
	Ca(2+) release mediated by ITPR1 is an essential mechanism during the early steps of myoblast differentiation

CELLULAR PROCESS

PHYSIOLOGICAL PROCESS

text	calcium ion transporter

PATHWAY

metabolism

signaling

signal transduction

a component

constituent of heterotetrameric channel with ITPR2 and ITPR3

INTERACTION

DNA

RNA

small molecule

protein	binding to ITPR2, ITPR3, CABP1 (in the brain)
	binding to CYCS during apoptosis
	interacting with RYR1, RYR2, SHANK1, SHANK3 and TRPC4
	interacting with TXNDC4 in a pH, redox-state and calcium-dependent manner
	interacting with PKD2 (modulate intracellular Ca2+ signaling)
	binding CIB1 (White 2006)
	CABP1 interacting with ITPR1 in the brain through a Ca2+-induced binding of the CABP1 C-domain to the N-terminal region of ITPR1 (residues 1-587)
	interaction juxtaposing the cytosolic RING domain of RNF170 with the cytosolic regions of activated ITPR1 that become ubiquitinated
	interaction between FKBP1A and RYR1, RYR3 and ITPR1
	ITPR1, ITPR2 enhanced gluconeogenic gene expression by promoting the calcineurin-mediated dephosphorylation of CRTC2
	CA8 is an allosteric inhibitor of ITPR1, which regulates intracellular calcium release fundamental to critical cellular functions including neuronal excitability, neurite outgrowth, neurotransmitter release
	DISC1 binds ITPR1 mRNA with ZNF385A, thereby regulating its dendritic transport for synaptic plasticity
	calcium-release channel that is inositol 1,4,5-trisphosphate (IP3) responsive

cell & other

REGULATION

repressed by

downregulated by muscarinic receptor activation

Other	highly sensitive to ATP mediating less regular Ca++ oscillations,in T lymphocyte
	phosphorylated by cAMP kinases
	regulated by TNF-alpha (in a neuronal environment modulates ITPR1 expression and intracellular Ca(2+) homeostasis) (Park 2009)
	RNF170, a E3 ligase, mediates ITPR1 ubiquitination

ASSOCIATED DISORDERS

corresponding disease(s)

SCA16 , SCA15 , GLSPS2 , CLA4

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function constitutional     --low   in neurodegenerative disease (olivopontocerebellar atrophy, cerebellar atrophy of Holmes type, Alzheimers disease, Friedreich's ataxia, cerebellopontine ataxia)

Susceptibility

Variant & Polymorphism

Candidate gene
Marker
Therapy target
	System Type Disorder Pubmed miscelleaneous pain   CA8 and ITPR1 represent new therapeutic targets for chronic pain

ANIMAL & CELL MODELS

mice with complete homozygosity for Itpr1 ablation suffer from severe epilepsy and ataxia and die either in utero or before weaning