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Seong-Ki Lee, Walter F Boron
Variant B of the electrogenic Na/HCO3 cotransporter (NBCe1-B) contributes to the vectorial transport of HCO3 - in epithelia (e.g., pancreatic ducts) and to the maintenance of intracellular pH in the central nervous systems (e.g., astrocytes). NBCe1-B has very low basal activity due to an autoinhibitory domain (AID), located, at least in part, in the unique portion (residues 1-85) of the cytosolic NH2 -terminus. Shcheynikov et al report that removing 23 amino acids (residues 40-62) stimulates NBCe1-B. Here, we test the hypothesis that a cationic cluster of 9 consecutive positively charged amino acids (residues 40-48) is a necessary part of the AID...
May 29, 2018: Journal of Physiology
Kyu Pil Lee, Hyun Jin Kim, Dongki Yang
Protein phosphatase 1 (PP1) is involved in various signal transduction mechanisms as an extensive regulator. The PP1 catalytic subunit (PP1c) recognizes and binds to PP1-binding consensus residues (FxxR/KxR/K) in NBCe1-B. Consequently, we focused on identifying the function of the PP1-binding consensus residue,922 FMDRLK927 , in NBCe1-B. Using site-directed mutagenesis and co-immunoprecipitation assays, we revealed that in cases where the residues were substituted (F922A, R925A, and K927A) or deleted (deletion of amino acids 922-927), NBCe1-B mutants inhibited PP1 binding to NBCe1-B...
January 2018: Korean Journal of Physiology & Pharmacology
Hideaki Ando, Katsuhiro Kawaai, Benjamin Bonneau, Katsuhiko Mikoshiba
The calcium ion (Ca2+ ) is a ubiquitous intracellular signaling molecule that regulates diverse physiological and pathological processes, including cancer. Increasing evidence indicates that oncogenes and tumor suppressors regulate the Ca2+ transport systems. Inositol 1,4,5-trisphosphate (IP3 ) receptors (IP3 Rs) are IP3 -activated Ca2+ release channels located on the endoplasmic reticulum (ER). They play pivotal roles in the regulation of cell death and survival by controlling Ca2+ transfer from the ER to mitochondria through mitochondria-associated ER membranes (MAMs)...
December 20, 2017: Advances in Biological Regulation
Maria Lisa Dentici, Sabina Barresi, Marta Nardella, Emanuele Bellacchio, Paolo Alfieri, Alessandro Bruselles, Francesca Pantaleoni, Alberto Danieli, Giancarlo Iarossi, Marco Cappa, Enrico Bertini, Marco Tartaglia, Ginevra Zanni
ITPR1 encodes an intracellular receptor for inositol 1,4,5-trisphosphate (InsP3) which is highly expressed in the cerebellum and is involved in the regulation of Ca2+ homeostasis. Missense mutations in the InsP3-binding domain (IRBIT) of ITPR1 are frequently associated with early onset cerebellar atrophy. Gillespie syndrome is characterized by congenital ataxia, mild to moderate intellectual disability and iris hypoplasia. Dominant or recessive ITPR1 mutations have been recently associated with this form of syndromic ataxia...
September 10, 2017: Gene
Katsuhiro Kawaai, Hideaki Ando, Nobuhiko Satoh, Hideomi Yamada, Naoko Ogawa, Matsumi Hirose, Akihiro Mizutani, Benjamin Bonneau, George Seki, Katsuhiko Mikoshiba
IRBIT [inositol 1,4,5-trisphosphate receptor (IP3 R) binding protein released with inositol 1,4,5-trisphosphate (IP3 )] is a multifunctional protein that regulates several target molecules such as ion channels, transporters, polyadenylation complex, and kinases. Through its interaction with multiple targets, IRBIT contributes to calcium signaling, electrolyte transport, mRNA processing, cell cycle, and neuronal function. However, the regulatory mechanism of IRBIT binding to particular targets is poorly understood...
April 11, 2017: Proceedings of the National Academy of Sciences of the United States of America
Benjamin Bonneau, Hideaki Ando, Katsuhiro Kawaai, Matsumi Hirose, Hiromi Takahashi-Iwanaga, Katsuhiko Mikoshiba
IRBIT is a molecule that interacts with the inositol 1,4,5-trisphosphate (IP3 )-binding pocket of the IP3 receptor (IP3 R), whereas the antiapoptotic protein, Bcl2l10, binds to another part of the IP3 -binding domain. Here we show that Bcl2l10 and IRBIT interact and exert an additive inhibition of IP3 R in the physiological state. Moreover, we found that these proteins associate in a complex in mitochondria-associated membranes (MAMs) and that their interplay is involved in apoptosis regulation. MAMs are a hotspot for Ca2+ transfer between endoplasmic reticulum (ER) and mitochondria, and massive Ca2+ release through IP3 R in mitochondria induces cell death...
December 20, 2016: ELife
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 Brankovic, 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 seven patients from four families (4/24, ∼16...
January 2017: 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
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