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Pil Whan Park, Jeong Yeal Ahn, Dongki Yang
Inositol-1,4,5-triphosphate [IP3] receptors binding protein released with IP3 (IRBIT) was previously reported as an activator of NBCe1-B. Recent studies have characterized IRBIT homologue S-Adenosylhomocysteine hydrolase-like 2 (AHCYL2). AHCYL2 is highly homologous to IRBIT (88%) and heteromerizes with IRBIT. The two important domains in the N-terminus of AHCYL2 are a PEST domain and a coiled-coil domain which are highly comparable to those in IRBIT. Therefore, in this study, we tried to identify the role of those domains in mouse AHCYL2 (Ahcyl2), and we succeeded in identifying PEST domain of Ahcyl2 as a regulation region for NBCe1-B activity...
July 2016: Korean Journal of Physiology & Pharmacology
Peijian He, Luqing Zhao, Yi Ran No, Serhan Karvar, C Chris Yun
Na(+)/H(+) exchanger (NHE)3, a major Na(+) transporter in the luminal membrane of the proximal tubule, is subject to ANG II regulation in renal Na(+)/fluid absorption and blood pressure control. We have previously shown that inositol 1,4,5-trisphosphate receptor-binding protein released with inositol 1,4,5-trisphosphate (IRBIT) mediates ANG II-induced exocytosis of NHE3 in cultured proximal tubule epithelial cells. In searching for scaffold protein(s) that coordinates with IRBIT in NHE3 trafficking, we found that NHE regulatory factor (NHERF)1, NHE3, and IRBIT proteins were coexpressed in the same macrocomplexes and that loss of ANG II type 1 receptors decreased their expression in the renal brush-border membrane...
August 1, 2016: American Journal of Physiology. Renal Physiology
S Barresi, M Niceta, P Alfieri, V Brankovich, G Piccini, A Bruselles, M R Barone, R Cusmai, M Tartaglia, E Bertini, G Zanni
Congenital Ataxias are nonprogressive neurological disorders characterized by neonatal hypotonia, developmental delay and ataxia, variably associated with intellectual disability and other neurological or extraneurological features. We performed trio-based whole exome sequencing of 12 families with congenital cerebellar and/or vermis atrophy in parallel with targeted next-generation sequencing of known ataxia genes (CACNA1A, ITPR1, KCNC3, ATP2B3 and GRM1) in 12 additional patients with a similar phenotype. Novel pathological mutations of ITPR1 (inositol 1,4,5-trisphosphate receptor, type 1) were found in 7 patients from 4 families (4/24, ~16,8%) all localized in the IRBIT (inositol triphosphate receptor binding protein) domain which plays an essential role in the regulation of neuronal plasticity and development...
April 7, 2016: Clinical Genetics
Yon Soo Jeong, Jeong Hee Hong
Anion exchanger 2 (AE2) has a critical role in epithelial cells and is involved in the ionic homeostasis such as Cl(-) uptake and HCO3(-) secretion. However, little is known about the regulatory mechanism of AE2. The main goal of the present study was to investigate potential regulators, such as spinophilin (SPL), inositol-1,4,5-trisphosphate [IP3] receptors binding protein released with IP3 (IRBIT), STE20/SPS1-related proline/alanine-rich kinase (SPAK) kinase, and carbonic anhydrase XII (CA XII). We found that SPL binds to AE2 and markedly increased the Cl(-)/HCO3(-) exchange activity of AE2...
2016: Channels
Hideaki Ando, Matsumi Hirose, Laura Gainche, Katsuhiro Kawaai, Benjamin Bonneau, Takeshi Ijuin, Toshiki Itoh, Tadaomi Takenawa, Katsuhiko Mikoshiba
Phosphatidylinositol phosphate kinases (PIPKs) are lipid kinases that generate phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2), a critical lipid signaling molecule that regulates diverse cellular functions, including the activities of membrane channels and transporters. IRBIT (IP3R-binding protein released with inositol 1,4,5-trisphosphate) is a multifunctional protein that regulates diverse target proteins. Here, we report that IRBIT forms signaling complexes with members of the PIPK family. IRBIT bound to all PIPK isoforms in heterologous expression systems and specifically interacted with PIPK type Iα (PIPKIα) and type IIα (PIPKIIα) in mouse cerebellum...
2015: PloS One
Heike Borth, Nele Weber, Dorke Meyer, Andrea Wartenberg, Elisabeth Arlt, Susanna Zierler, Andreas Breit, Gunther Wennemuth, Thomas Gudermann, Ingrid Boekhoff
Besides its capacity to inhibit the 1,4,5-trisphosphate (IP3) receptor, the regulatory protein IRBIT (IP3 receptor binding protein released with IP3) is also able to control the activity of numerous ion channels and electrolyte transporters and thereby creates an optimal electrolyte composition of various biological fluids. Since a reliable execution of spermatogenesis and sperm maturation critically depends on the establishment of an adequate microenvironment, the expression of IRBIT in male reproductive tissue was examined using immunohistochemical approaches combined with biochemical fractionation methods...
May 2016: Journal of Cellular Physiology
Peijian He, Luqing Zhao, Lixin Zhu, Edward J Weinman, Roberto De Giorgio, Michael Koval, Shanthi Srinivasan, C Chris Yun
Diarrhea is one of the troublesome complications of diabetes, and the underlying causes of this problem are complex. Here, we investigated whether altered electrolyte transport contributes to diabetic diarrhea. We found that the expression of Na+/H+ exchanger NHE3 and several scaffold proteins, including NHE3 regulatory factors (NHERFs), inositol trisphosphate (IP₃) receptor-binding protein released with IP₃ (IRBIT), and ezrin, was decreased in the intestinal brush border membrane (BBM) of mice with streptozotocin-induced diabetes...
September 2015: Journal of Clinical Investigation
Katsuhiro Kawaai, Akihiro Mizutani, Hirotaka Shoji, Naoko Ogawa, Etsuko Ebisui, Yukiko Kuroda, Shigeharu Wakana, Tsuyoshi Miyakawa, Chihiro Hisatsune, Katsuhiko Mikoshiba
Inositol 1,4,5-trisphosphate receptor (IP3R) binding protein released with IP3 (IRBIT) contributes to various physiological events (electrolyte transport and fluid secretion, mRNA polyadenylation, and the maintenance of genomic integrity) through its interaction with multiple targets. However, little is known about the physiological role of IRBIT in the brain. Here we identified calcium calmodulin-dependent kinase II alpha (CaMKIIα) as an IRBIT-interacting molecule in the central nervous system. IRBIT binds to and suppresses CaMKIIα kinase activity by inhibiting the binding of calmodulin to CaMKIIα...
April 28, 2015: Proceedings of the National Academy of Sciences of the United States of America
Nikolay Shcheynikov, Aran Son, Jeong Hee Hong, Osamu Yamazaki, Ehud Ohana, Ira Kurtz, Dong Min Shin, Shmuel Muallem
Cl(-) is a major anion in mammalian cells involved in transport processes that determines the intracellular activity of many ions and plasma membrane potential. Surprisingly, a role of intracellular Cl(-) (Cl(-) in) as a signaling ion has not been previously evaluated. Here we report that Cl(-) in functions as a regulator of cellular Na(+) and HCO3 (-) concentrations and transepithelial transport through modulating the activity of several electrogenic Na(+)-HCO3 (-) transporters. We describe the molecular mechanism(s) of this regulation by physiological Cl(-) in concentrations highlighting the role of GXXXP motifs in Cl(-) sensing...
January 20, 2015: Proceedings of the National Academy of Sciences of the United States of America
Katsuhiko Mikoshiba
IP3 receptor (IP3R) was found to release Ca(2+) from non-mitochondrial store but the exact localization and the mode of action of IP3 remained a mystery. IP3R was identified to be P400 protein, a protein, which was missing in the cerebellum of ataxic mutant mice lacking Ca(2+) spikes in Pukinje cells. IP3R was an IP3 binding protein and was a Ca(2+) channel localized on the endoplasmic reticulum. Full-length cDNA of IP3R type 1 was initially cloned and later two other isoforms of IP3R (IP3R type 2 and type 3) were cloned in vertebrates...
January 2015: Advances in Biological Regulation
(no author information available yet)
IRBIT inhibits ribonucleotide reductase (RNR) by stabilizing dATP binding to the RNR activity site.
November 2014: Cancer Discovery
Alexei Arnaoutov, Mary Dasso
Ribonucleotide reductase (RNR) supplies the balanced pools of deoxynucleotide triphosphates (dNTPs) necessary for DNA replication and maintenance of genomic integrity. RNR is subject to allosteric regulatory mechanisms in all eukaryotes, as well as to control by small protein inhibitors Sml1p and Spd1p in budding and fission yeast, respectively. Here, we show that the metazoan protein IRBIT forms a deoxyadenosine triphosphate (dATP)-dependent complex with RNR, which stabilizes dATP in the activity site of RNR and thus inhibits the enzyme...
September 19, 2014: Science
Malini Ahuja, Archana Jha, Jozsef Maléth, Seonghee Park, Shmuel Muallem
The Ca(2+) and cAMP/PKA pathways are the primary signaling systems in secretory epithelia that control virtually all secretory gland functions. Interaction and crosstalk in Ca(2+) and cAMP signaling occur at multiple levels to control and tune the activity of each other. Physiologically, Ca(2+) and cAMP signaling operate at 5-10% of maximal strength, but synergize to generate the maximal response. Although synergistic action of the Ca(2+) and cAMP signaling is the common mode of signaling and has been known for many years, we know very little of the molecular mechanism and mediators of the synergism...
June 2014: Cell Calcium
Hideaki Ando, Katsuhiro Kawaai, Katsuhiko Mikoshiba
IRBIT (also called AHCYL1) was originally identified as a binding protein of the intracellular Ca(2+) channel inositol 1,4,5-trisphosphate (IP3) receptor and functions as an inhibitory regulator of this receptor. Unexpectedly, many functions have subsequently been identified for IRBIT including the activation of multiple ion channels and ion transporters, such as the Na(+)/HCO3(-) co-transporter NBCe1-B, the Na(+)/H(+) exchanger NHE3, the Cl(-) channel cystic fibrosis transmembrane conductance regulator (CFTR), and the Cl(-)/HCO3(-) exchanger Slc26a6...
October 2014: Biochimica et Biophysica Acta
Soichiro Yamaguchi, Toru Ishikawa
Although AHCYL2 (long-IRBIT) is highly homologous to IRBIT, which regulates ion-transporting proteins including the electrogenic Na(+)-HCO3(-) cotransporter NBCe1-B, its functions are poorly understood. Here, we found that AHCYL2 interacts with NBCe1-B in bovine parotid acinar cells using yeast two-hybrid, immunofluorescence confocal microscopy and co-immunoprecipitation analyses. Whole-cell patch-clamp experiments revealed that co-expression of AHCYL2 reduces the apparent affinity for intracellular Mg(2+) in inhibition of NBCe1-B currents specifically in a HCO3(-)-deficient cellular condition...
March 3, 2014: FEBS Letters
Jeong Hee Hong, Seonghee Park, Nikolay Shcheynikov, Shmuel Muallem
A central function of epithelia is the control of the volume and electrolyte composition of bodily fluids through vectorial transport of electrolytes and the obligatory H2O. In exocrine glands, fluid and electrolyte secretion is carried out by both acinar and duct cells, with the portion of fluid secreted by each cell type varying among glands. All acinar cells secrete isotonic, plasma-like fluid, while the duct determines the final electrolyte composition of the fluid by absorbing most of the Cl(-) and secreting HCO3 (-)...
August 2014: Pflügers Archiv: European Journal of Physiology
Tien Manh Tran, Moon-Yong Park, Jiyeon Lee, Jun-Seok Bae, Sung-Min Hwang, Se-Young Choi, Katsuhiko Mikoshiba, Kyungpyo Park
Expression of inositol-1,4,5-trisphosphate (IP3) receptor-binding protein (IRBIT) has been reported in epithelial cells. However, its role in pHi regulation is not well understood. In this study, we investigated the role of IRBIT in pHi regulation, mediated by Na(+)/H(+) exchangers (NHEs), in salivary glands. We measured pHi recovery from cell acidification in BCECF-loaded salivary HSG cells. Western blot and co-immunoprecipitation (CO-IP) assays were also performed, showing that NHE1, 2 and 3 are expressed, and IRBIT binds to NHE3...
July 19, 2013: Biochemical and Biophysical Research Communications
Seonghee Park, Nikolay Shcheynikov, Jeong Hee Hong, Changyu Zheng, Suk Hyo Suh, Katsuhiro Kawaai, Hideaki Ando, Akihiro Mizutani, Takaya Abe, Hiroshi Kiyonari, George Seki, David Yule, Katsuhiko Mikoshiba, Shmuel Muallem
BACKGROUND & AIMS: The cyclic adenosine monophosphate (cAMP) and Ca(2+) signaling pathways synergize to regulate many physiological functions. However, little is known about the mechanisms by which these pathways interact. We investigated the synergy between these signaling pathways in mouse pancreatic and salivary gland ducts. METHODS: We created mice with disruptions in genes encoding the solute carrier family 26, member 6 (Slc26a6(-/-) mice) and inositol 1,4,5-triphosphate (InsP3) receptor-binding protein released with InsP3 (Irbit(-/-)) mice...
July 2013: Gastroenterology
Jeong Hee Hong, Dongki Yang, Nikolay Shcheynikov, Ehud Ohana, Dong Min Shin, Shmuel Muallem
Fluid and HCO3(-) secretion is a vital function of secretory epithelia, involving basolateral HCO3(-) entry through the Na(+)-HCO3(-) cotransporter (NBC) NBCe1-B, and luminal HCO3(-) exit mediated by cystic fibrosis transmembrane conductance regulator (CFTR) and solute carrier family 26 (SLC26) Cl(-)/HCO3(-) exchangers. HCO3(-) secretion is highly regulated, with the WNK/SPAK kinase pathway setting the resting state and the IRBIT/PP1 pathway setting the stimulated state. However, we know little about the relationships between the WNK/SPAK and IRBIT/PP1 sites in the regulation of the transporters...
March 5, 2013: Proceedings of the National Academy of Sciences of the United States of America
Wooyoung Jeong, Jinyoung Kim, Suzie E Ahn, Sang In Lee, Fuller W Bazer, Jae Yong Han, Gwonhwa Song
S-adenosylhomocysteine hydrolase-like protein 1 (AHCYL1), also known as IP(3) receptor-binding protein released with IP(3) (IRBIT), regulates IP(3)-induced Ca(2+) release into the cytoplasm of cells. AHCYL1 is a critical regulator of early developmental stages in zebrafish, but little is known about the function of AHCYL1 or hormonal regulation of expression of the AHCYL1 gene in avian species. Therefore, we investigated differential expression profiles of the AHCYL1 gene in various adult organs and in oviducts from estrogen-treated chickens...
2012: PloS One
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