HGNC Approved Gene Symbol: ITPR2
SNOMEDCT: 1187178004;
Cytogenetic location: 12p11.23 Genomic coordinates (GRCh38): 12:26,335,352-26,833,194 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12p11.23 | ?Anhidrosis, isolated, with normal sweat glands | 106190 | Autosomal recessive | 3 |
Yamamoto-Hino et al. (1994) cloned cDNAs coding for human type 2 and type 3 inositol 1,4,5-triphosphate receptors. The complete nucleotide sequences for both receptors were determined. The human type 2 (ITPR2) and type 3 (ITPR3; 147267) receptors are 2,710 amino acids and 2,671 amino acids long, respectively, and have significant sequence homologies as well as structural similarities, including the 6 membrane-spanning regions near the C termini. Yamamoto-Hino et al. (1994) found that the type 3 receptor was present in all hematopoietic and lymphoma cell lines tested, while the type 2 receptor was expressed in only particular cell types.
By isotopic in situ hybridization, Yamamoto-Hino et al. (1994) mapped the ITPR2 and ITPR3 genes to chromosome 12p11 and 6p21, respectively.
Wei et al. (2009) visualized high-calcium microdomains ('calcium flickers') and their patterned activation in migrating human embryonic lung fibroblasts. Calcium flicker activity is dually coupled to membrane tension, by means of TRPM7 (600692), a stretch-activated calcium-permeant channel of the transient receptor potential superfamily, and chemoattractant signal transduction, by means of type 2 inositol-1,4,5-triphosphate receptors. Interestingly, calcium flickers are most active at the leading lamella of migrating cells, displaying a 4:1 front-to-rear polarization opposite to the global calcium gradient. When exposed to a platelet-derived growth factor (see 173430) gradient perpendicular to cell movement, asymmetric calcium flicker activity developed across the lamella and promoted the turning of migrating fibroblasts. Wei et al. (2009) concluded that their findings showed how the exquisite spatiotemporal organization of calcium microdomains can orchestrate complex cellular processes such as cell migration.
Wang et al. (2012) showed in mice that glucagon stimulates CRTC2 (608972) dephosphorylation in hepatocytes by mobilizing intracellular calcium stores and activating the calcium/calmodulin-dependent ser/thr-phosphatase calcineurin (PPP3CA; 114105). Glucagon increased cytosolic calcium concentration through the PKA-mediated phosphorylation of inositol-1,4,5-trisphosphate receptors (InsP3Rs) (ITPR1, 147265; ITPR2; ITPR3, 147267), which associated with CRTC2. After their activation, InsP3Rs enhanced gluconeogenic gene expression by promoting the calcineurin-mediated dephosphorylation of CRTC2. During feeding, increases in insulin signaling reduced CRTC2 activity via the AKT (164730)-mediated inactivation of InsP3Rs. InsP3R activity was increased in diabetes, leading to upregulation of the gluconeogenic program. As hepatic downregulation of InsP3Rs and calcineurin improved circulating glucose levels in insulin resistance, these results demonstrated how interactions between cAMP and calcium pathways at the level of the InsP3R modulate hepatic glucose production under fasting conditions and in diabetes.
By whole-genome sequencing in a consanguineous Pakistani family with isolated anhidrosis and morphologically normal eccrine sweat glands (ANHD; 106190), Klar et al. (2014) identified a homozygous missense mutation in the ITPR2 gene (G2498S; 600144.0001). The mutation, which occurred at a highly conserved residue, was not found in 200 Swedish and 200 Pakistani control chromosomes, in 850 in-house exomes, or in the Exome Variant Server database.
Futatsugi et al. (2005) generated mice lacking ITPR2 or ITPR3 or both by targeted disruption. The single-gene mutants were viable and showed no distinct abnormalities in appearance, at least for several months after birth. Mutant mice lacking both of these ITPRs were also viable during the embryonic period. At birth, double mutants were indistinguishable from nonhomozygous littermates, but double mutants gained less body weight after birth. After the weaning period, around postnatal day 20, double-knockout mice began losing weight and died by the fourth week of age. Double mutants did not eat dry food, but when fed wet mash beginning on postnatal day 20, they consumed this type of food and survived thereafter. Body weight increases of the double mutants were still smaller than those of their non-double-mutant littermates, despite consuming the same quantity of food. Futatsugi et al. (2005) found that these double mutants had exocrine dysfunction which caused difficulties with nutrient digestion. Severely impaired calcium signaling in acinar cells of the salivary glands and the pancreas in the double mutants ascribed the secretion deficits to a lack of intracellular calcium release. Despite a normal caloric intake, the double mutants were hypoglycemic and lean. Futatsugi et al. (2005) concluded that these results revealed ITPR2 and ITPR3 as key molecules in exocrine physiology underlying energy metabolism and animal growth.
By analyzing eccrine glands in the paws of Itpr2-null mice, Klar et al. (2014) observed a 3-fold reduction in the number of pilocarpine-responsive sweat glands. The sweat glands of these mice showed a significant reduction in Ca(2+) response following acetylcholine stimulation compared with those of wildtype mice. The Itpr2-null mice retained some residual sweat production, in contrast to the human phenotype of anhidrosis. Klar et al. (2014) suggested that this phenotypic discrepancy may be due to differences between humans and mice in the expression of the 3 ITPR isoforms, as well as to the different stimuli used to provoke sweat production in Itpr2-null mice.
By whole-genome sequencing of a consanguineous Pakistani family with isolated anhidrosis and morphologically normal sweat glands (ANHD; 106190), Klar et al. (2014) identified a homozygous c.7492G-A transition (c.7492G-A, NM_002223.2) in the ITPR2 gene, resulting in a gly2498-to-ser (G2498S) substitution at a highly conserved residue, in all 5 affected family members. The mutation was found in heterozygous state in 3 parents and 2 healthy sibs; the other parent and another sib were unavailable for testing. The mutation was not found in 200 Swedish and 200 Pakistani control chromosomes, in 850 in-house exomes, or in the Exome Variant Server database. Klar et al. (2014) expressed the G2498S mutation in chicken B lymphocytes lacking endogenous ITPR genes. Cells expressing the mutation showed a complete loss of Ca(2+) response upon stimulation, despite Ca(2+) stores similar to those of control cells expressing wildtype ITPR2. The results suggested that intracellular Ca(2+) release by ITPR2 in clear cells of the sweat glands is important for eccrine sweat production and the G2498S mutation causes a loss of function.
Futatsugi, A., Nakamura, T., Yamada, M. K., Ebisui, E., Nakamura, K., Uchida, K., Kitaguchi, T., Takahashi-Iwanaga, H., Noda, T., Aruga, J., Mikoshiba, K. IP(3) receptor types 2 and 3 mediate exocrine secretion underlying energy metabolism. Science 309: 2232-2234, 2005. [PubMed: 16195467] [Full Text: https://doi.org/10.1126/science.1114110]
Klar, J., Hisatsune, C., Baig, S. M., Tariq, M., Johansson, A. C. V., Rasool, M., Malik, N. A., Ameur, A., Sugiura, K., Feuk, L., Mikoshiba, K., Dahl, N. Abolished InsP(3)R2 function inhibits sweat secretion in both humans and mice. J. Clin. Invest. 124: 4773-4780, 2014. [PubMed: 25329695] [Full Text: https://doi.org/10.1172/JCI70720]
Wang, Y., Li, G., Goode, J., Paz, J. C., Ouyang, K., Screaton, R., Fischer, W. H., Chen, J., Tabas, I., Montminy, M. Inositol-1,4,5-trisphosphate receptor regulates hepatic gluconeogenesis in fasting and diabetes. Nature 485: 128-132, 2012. [PubMed: 22495310] [Full Text: https://doi.org/10.1038/nature10988]
Wei, C., Wang, X., Chen, M., Ouyang, K., Song, L.-S., Cheng, H. Calcium flickers steer cell migration. Nature 457: 901-905, 2009. [PubMed: 19118385] [Full Text: https://doi.org/10.1038/nature07577]
Yamamoto-Hino, M., Sugiyama, T., Hikichi, K., Mattei, M. G., Hasegawa, K., Sekine, S., Sakurada, K., Miyawaki, A., Furuichi, T., Hasegawa, M., Mikoshiba, K. Cloning and characterization of human type 2 and type 3 inositol 1,4,5-triphosphate receptors. Receptors Channels 2: 9-22, 1994. [PubMed: 8081734]