(excerpt)
 Hormones and neurotransmitters regulate cell functions by binding to their receptors, which activate intracellular signaling and produce the physiological response [1]. There are several intracellular pathways, including but not limited to, leading to the activation of protein kinases, phosphatases and increase in intracellular calcium (Ca2+) [1]

Bouyer, Patrice G

Cook, Kelli

Petreska, Natasa

English

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Valparaiso University
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Biology Faculty Publications Department of Biology
2-22-2017
IRBIT a Master Regulator of Cell Physiology
Kelli Cook
Valparaiso University
Natasa Petreska
Valparaiso University
Patrice G. Bouyer
Valparaiso University
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Recommended Citation
Cook, Kelli; Petreska, Natasa; and Bouyer, Patrice G., "IRBIT a Master Regulator of Cell Physiology" (2017). Biology Faculty
Publications. 35.
https://scholar.valpo.edu/bio_fac_pub/35
MOJ Cell Science & Report 
IRBIT a Master Regulator of Cell Physiology
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proteins are known to bind to the IP3R and regulate Ca2+ release [3,4]. These include IRBIT (inositol-1,4,5-trisphosphate (IP3) receptors binding protein released with IP3), a protein discovered by Mikoshiba’s group [4,5]. Over the past decade IRBIT has emerged not only as an IP3R regulator but also as an important regulator of other cellular functions.
IRBIT Regulates Intracellular Ca2+ Release from IP3RThe IP3R interacts with specific proteins (e.g. Huntingtin, RACK1) and forms a macrocomplex that is believed to provide 
the diversity and specificity of the Ca2+signaling [4]. IRBIT was discovered while searching for novel binding partners of the IP3R [5]. IRBIT negatively regulates the IP3R by competing with IP3 [6]. IRBIT interaction with the IP3R (thus regulation of IP3 binding to its receptor) is decreased when IRBIT is phosphorylated as protein phosphatase (e.g. protein phosphatase 1) lowers IRBIT 
affinity to the IP3R. Furthermore, phosphorylation of IRBIT’s serine 68 plays a critical role in IRBIT inhibiting IP3 from binding to its receptor [6,7]. In addition to the phosphorylation state of 
IRBIT, two motifs (PEST and PDZ) were identified by in-silico analysis [8]. Pull-down assays with IRBIT missing the PEST or PDZ motif demonstrated that these two motifs are important for the binding of IRBIT to the IP3R [8]. 
IRBIT a Regulator of Membrane TransporterAs pointed above, IRBIT is released from the IP3R after IP3 binds to its receptor. Thus Mikoshiba’s group hypothesized that IRBIT could be a new signaling molecule that interacts with downstream targets. By screening proteins that can bind to IRBIT they found that IRBIT interacts with the electrogenic sodium bicarbonate, NBCe1-B variant (aka pancreatic isoform). Using a heterologous system to co-express IRBIT and NBCe1-B, they showed by electrophysiological measurements that the transport activity of NBCe1-B is substantially increased in the presence of IRBIT [9]. Another study demonstrated that IRBIT increases NBCe1-B activity by masking in part the auto inhibitory domain of NBCe1-B [10]. These experiments suggest that IRBIT 
by increasing the activity of NBCe1-B, plays an important role in acid-base homeostasis.
The Na/H exchanger 3 (NHE3) participates in sodium (Na+) reabsorption in the kidney. Angiotensin II (a hormone elevating Ca2+ via IP3) increases Na+ reabsorption by stimulating NHE3 in the kidney [11], but the mechanisms by which angiotensin II 
activates NHE3 are not clear. Using a yeast two-hybrid system 
He et al. found that IBIRT interacts with NHE3 [12]. In addition, knocking down IRBIT abrogates the stimulatory effect of Ca2+ 
and angiotensin II on the activity of NHE3 [12,13]. These studies provide new ways of better understanding how angiotensin II,via the Ca2+ signaling stimulates Na+ reabsorption in the kidney. 
In the pancreatic duct, fluid secretion is driven by an active 
transcellular secretion of bicarbonate (HCO–3). The basolateral 
NBCe1-B pumps HCO–3 inside the cell while the apical cystic 
fibrosis transmembrane regulator (CFTR) and Cl/HCO3 exchanger 
SLC26a6 secrete HCO–3 in the pancreatic duct lumen. In addition to NBCe1-B, it was found that IRBIT binds to CFTR and SLC26a6 and increases transport activity of both transporters. The authors proposed that IRBIT coordinates the activity of basolateral and 
apical transporters involved in HCO–3-mediated fluid secretion [14,15]. The results from these studies describe a new process allowing the crosstalk between the apical and basolateral membrane. Finally, IRBIT has also been reported to bind with the Na-K-2Cl cotransporter 1 (NKCC1) in human T84 cells. Silencing IRBIT in this model decreased the cAMP-stimulated Cl− secretion presumably by decreasing the activity of NKCC1 [16].
IRBIT a Synergistic Mediator of the cAMP and Ca2+ 
Signaling PathwayIn secretory epithelia, Ca2+ and cAMP signaling pathways control secretion. Both pathways can have an additive or synergistic action [17-19]. For a more detailed discussion on how intracellular Ca2+ potentiates the cAMP pathway and vice versa and synergistic effect of Ca2+ and cAMP we refer the reader to 
 Volume 4 Issue 1 - 2017
 
Department of Biology, Valparaiso University, USA
*Corresponding author: Patrice G Bouyer, Department of Biology, Valparaiso University, USA Tel: (219) 464-5487; Fax: (219) 464-5489; Email: 
Received: February 13, 2017 | Published: February 22, 2017
Editorial
MOJ Cell Sci Rep 2017, 4(1): 00078
Introduction
Hormones and neurotransmitters regulate cell functions by binding to their receptors, which activate intracellular signaling and produce the physiological response [1]. There are several intracellular pathways, including but not limited to, leading to the activation of protein kinases, phosphatases and increase in intracellular calcium (Ca2+) [1]. Calcium signaling controls many cellular responses (e.g. exocytosis, cell spreading, muscle contraction). Therefore it is important to understand the mechanisms regulating intracellular Ca2+. Two major sources exist to raise intracellular ca2+: extracellular medium and internal stores (e.g., endoplasmic reticulum, mitochondria). While Ca2+ channels at the plasma membrane regulate Ca2+ entry in the cell, the inositol-1,4,5-trisphosphate receptor (IP3R) controls the release of Ca2+ from the endoplasmic reticulum [2,3]. Many 
Citation: Cook K, Petreska N, Bouyer PG (2017) IRBIT a Master Regulator of Cell Physiology. MOJ Cell Sci Rep 4(1): 00078. DOI: 10.15406/mojcsr.2017.04.00078
IRBIT a Master Regulator of Cell Physiology 2/3
Copyright:©2017 Cook et al.
the review by Abuja et al. [19]. To date, the mechanistic details behind the synergistic action of Ca2+ and cAMP remain elusive, but work in the pancreatic duct and the salivary glands has shown that IRBIT can mediate the synergistic activation of the CFTR and SLC26a6 by cAMP and Ca2+ [15]. Further work is now needed to test whether IRBIT mediates the synergistic effect of cAMP and Ca2+ in other tissues and whether additional proteins participate in the synergistic mechanism.
Other Functions of IRBITBecause of the numerous downstream targets of Ca2+ it is not surprising that IRBIT has additional roles other than the ones discussed above. For instance, IRBIT interacts with the cleavage 
and polyadenylation specificity factor, which plays a role in mRNA processing. This study suggests that IRBIT could regulate gene expression [20]. IRBIT also binds to the phosphatidyl inositol phosphate kinase members, who are potent regulators of ion transporters and would provide another level of regulation for electrolyte and solute transport in cells [21]. IRBIT has been reported to inhibit the calcium calmodulin-dependent kinase II alpha in the brain and thus, would contribute to the regulation of the amount of catecholamine in the brain [22]. IRBIT null mice show abnormal social behavior and hyperactivity that can be attributed to the level of catecholamine [22]. Most recently IRBIT has been demonstrated to be involved with cell death by blocking the Bcl2l10 protein and facilitating large movements of Ca2+ to the mitochondria and thus promoting apoptosis [23]. 
ConclusionAlthough some of IRBIT’s cellular functions have started to be uncovered, many unknowns about IRBIT still exist. For instance, there are two isoforms of IRBIT a short and long N-terminus IRBIT [24]. Most of the studies have focused on the short N-terminus, but the long N-terminus is also capable of binding to NBCe1-B and decreases the Mg2+-sensitivity of NBCe1-B inhibition during low 
HCO–3 [25]. The expression and distribution of the two isoforms within tissues is not known. It remains to be determined whether the long and short IRBIT share common target proteins, and if so what is the impact of each isoform on the function of the target protein. Experiments have shown that a phosphorylation state of IRBIT is critical for carrying out its functional role; however, beside this rapid regulation we know very little about the rapid regulation of IRBIT by other proteins (e.g. kinases) or IRBIT gene expression. One study shows that in avian’s oviduct, estrogen agonist induced IRBIT expression in luminal and glandular epithelial cells of the oviduct [26]. Because of IRBIT involvement in Na+ and HCO–3 transport we may expect that acid-base status (e.g. metabolic acidosis, and alkalosis), blood pressure or hormones involved in Na+ homeostasis (e.g. aldosterone, angiotensin II) influence IRBIT expression. Because of its role as a third messenger released from the IP3R it is expected that IRBIT will play essential roles in health and diseases.
AcknowledgementThe authors would like to thank Lynn Wellsand for her administrative assistance. PBG is supported by the Start up funds from Valparaiso University Art & Science College and the Wheat 
Ridge Ministries O.P. Kretzmann Grant for Research in the Healing Arts and Sciences.
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Citation: Cook K, Petreska N, Bouyer PG (2017) IRBIT a Master Regulator of Cell Physiology. MOJ Cell Sci Rep 4(1): 00078. DOI: 10.15406/mojcsr.2017.04.00078
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Copyright:©2017 Cook et al.
15.  Park S, Shcheynikov N, Hong JH, Zheng C, Suh SH, et al. (2013) IRBIT mediates synergy between Ca2+ and cAMP signaling pathways during epithelial transport in mice. Gastroenterology 145(1): 232-241.16. Tang X, Tang J, Mykoniatis A, Matthews JB, Bouyer P, et al. (2010) W1779 Regulation of chloride secretion in the colonic crypt cell line T84 by Inositol 1, 4, 5-trisphosphate (IP3) Receptor-Binding protein released with IP3 regulates (IRBIT). Gastroenterology 138(5 Suppl 1): 738.17.  Cartwright CA, McRoberts JA, Mandel KG, Dharmsathaphorn K (1985) Synergistic action of cyclic adenosine monophosphate- and calcium-mediated chloride secretion in a colonic epithelial cell line. J Clin Invest 76(5): 1837-1842.18.  Vajanaphanich M, Schultz C, Tsien RY, Traynor Kaplan AE, Pandol SJ, et al. (1995) Cross-talk between calcium and cAMP-dependent intracellular signaling pathways. Implications for synergistic secretion in T84 colonic epithelial cells and rat pancreatic acinar cells. J Clin Invest 96(1): 386-393.19.  Ahuja M, Jha A, Maléth J, Park S, Muallem S (2014) cAMP and Ca2+ signaling in secretory epithelia: crosstalk and synergism. Cell Calcium 55(6): 385-393.20.  Kiefer H, Mizutani A, Iemura S, Natsume T, Ando H, et al. (2009) Inositol 1,4,5-triphosphate receptor-binding protein released with inositol 1,4,5-triphosphate (IRBIT) associates with components of the mRNA 3’ processing machinery in a phosphorylation-
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