Explore chapters and articles related to this topic
Roles of membrane and nuclear estrogen receptors in spermatogenesis
Published in C. Yan Cheng, Spermatogenesis, 2018
Paul S. Cooke, Manjunatha K. Nanjappa, Sergei G. Tevosian, Rex A. Hess
In agreement with previous data, we observed a strong (~14-fold) downregulation of Slc9a3 RNA in NOER epididymis (Figure 9.2, Tevosian et al., unpublished) confirming that mRNA signaling is required for Slc9a3 expression. Aqp1 was also downregulated while expression of the ubiquitous Aqp4 was unchanged. Carbonic anhydrase 14 (Car14, CA-XIV), the primary carbonic anhydrase present on the luminal surface in the proximal epididymis, was unchanged, and expression of cotransporter SLC4A4 was slightly elevated (Figure 9.2). Collectively, these findings suggest that, similar to Esr1KO mice, reduced expression of Slc9A3 and Aqp1 could be involved in NOER male reproductive abnormalities.
Profiling gene expression dynamics underpinning conventional testing approaches to better inform pre-clinical evaluation of an age appropriate spironolactone formulation
Published in Pharmaceutical Development and Technology, 2021
Craig Russell, Majad Hussain, David Huen, Ayesha S. Rahman, Afzal R. Mohammed
When considering permeability through the intestinal epithelial, it is important to consider the inherent properties which limit absorption. This includes the physiochemical makeup of the cell membranes as well as the tight junctions between the cells which are tightly regulated and highly selective. For instance, SLC9A3R1 is of interest when examining intestinal permeability as it codes for SLC9A3 Regulator 1 (NHERF1). This protein interacts with villin and actin which function as linkers between integral membrane and cytoskeletal proteins involved with the formation and maintenance of tight junctions (Castellani et al. 2012). Tight junctions exist between intestinal enterocytes and are one of the key limiters in modulating paracellular intestinal permeability and maintaining membrane barrier function. Although spironolactone is not reported to be absorbed paracellularly this may indicate that tight junctions were closed in response to exposure to the spironolactone formulation. Evidence of cellular response to formulation exposure can also be seen through expression changes in genes involved in signalling pathways including SLC25A6, SLC3A2, SLC7A5, SLC27A1, and SLC2A2. cGMP-PKG signalling has been shown previously to control dynamic responses of tight junctions in the blood brain barrier (BBB) through voltage-dependent anion channel protein 1 which is coded for by SLC25A6 (González-Mariscal et al. 2008). The tight junctions that form the paracellular barrier at the BBB and intestinal enterocytes display remarkable molecular similarities (Daneman and Rescigno 2009).
Recent advances in potential targets for eosinophilic esophagitis treatments
Published in Expert Review of Clinical Immunology, 2020
Salvatore Oliva, Nurit P. Azouz, Laura Stronati, Marc E. Rothenberg
The solute carrier family 9, subfamily A, member 3 (SLC9A3), which encodes sodium-hydrogen exchanger member 3 (NHE3), is predominantly expressed in the apical membrane of the epithelium and functions as a regulator of electroneutral exchange, maintenance of intracellular pH (pHi), and regulation of cell volume. It has been shown that SLC9A3 expression is increased in EoE biopsies compared to controls; SLC9A3 increases the baseline pHi in epithelial cells, which in turn promotes DIS. Pharmacologic interventions targeting SLC9A3 function abrogate IL-13-induced barrier damage [36].
Genetic and transcriptional analysis of inflammatory bowel disease-associated pathways in patients with GUCY2C-linked familial diarrhea
Published in Scandinavian Journal of Gastroenterology, 2018
Rune R. Tronstad, Tatiana Polushina, Hans-Richard Brattbakk, Christine Stansberg, Hilde Løland von Volkmann, Kurt Hanevik, Eva Ellinghaus, Silje Fjellgård Jørgensen, Kari Merete Ersland, Khanh D.-C. Pham, Odd Helge Gilja, Nils Hovdenak, Trygve Hausken, Morten H. Vatn, Andre Franke, Per Morten Knappskog, Stephanie Le Hellard, Tom Hemming Karlsen, Torunn Fiskerstrand
The enrichment of association in IBD GWAS data was essentially driven by six genes encoding proteins related to regulation of CFTR (protein kinase A and AMPK) and electroneutral absorption of sodium chloride (DRA, NHE2-3 and NHERF3 [1,38] CFTR is a master regulator of electrolyte homeostasis in the intestine, integrating the function of GC-C [38] and the proteins involved in electroneutral absorption of sodium chloride [1,39]. GUCY2C is not flagged as an important gene driving the GSEA result for IBD, but activating mutations are very rare and will not be identified as risk variants in a GWAS study. The downstream effects of the activating GUCY2C mutation in FGDS are nevertheless activation of CFTR and inhibition of NHE3, i.e. net loss of sodium chloride to the intestine. Notably, GC-C related increase in cGMP is not the major pathway activating CFTR, but rather cyclic adenosine monophosphate activation of protein kinase A. This involves adenylyl cyclases as well as their inhibitory G-proteins [40], and IBD risk variants have been reported in several of these genes [41–43]. Our analysis of GWAS data does not provide information on whether the identified genetic variants contribute to an overall up- or down-regulated activity of the pathway. However, patients with congenital rare diseases and long standing high activity of the GC-C-CFTR pathway do have increased susceptibility for IBD (activating mutations in GUCY2C, loss of function mutations in SLC26A3 and SLC9A3) [2,5,13]. Monogenic disorders with low activity of this pathway don’t display such clear susceptibility (loss of function mutations in CFTR and GUCY2C) [44,45]. The question arises whether beneficial effects of short term GC-C activation [8,11] may be abolished and turn pro-inflammatory in a time- and/or dose-dependent manner. This is an important issue concerning ongoing trials with GC-C agonists as treatment for IBD [46].