Last update 01 Nov 2024

NHE5

Last update 01 Nov 2024

Basic Info

Synonyms

Na(+)/H(+) exchanger 5, NHE-5, NHE5

+ [7]

Introduction

Plasma membrane Na(+)/H(+) antiporter. Mediates the electroneutral exchange of intracellular H(+) ions for extracellular Na(+) in 1:1 stoichiometry, thus regulating intracellular pH homeostasis, in particular in neural tissues (PubMed:9933641, PubMed:10692428, PubMed:19276089, PubMed:24936055). Acts as a negative regulator of dendritic spine growth (PubMed:21551074). Plays a role in postsynaptic remodeling and signaling (PubMed:24006492, PubMed:21551074). Can also contribute to organellar pH regulation, with consequences for receptor tyrosine kinase trafficking (PubMed:24936055).

Drugs associated with NHE5

UTX-143

Target

NHE5

Mechanism

NHE5 inhibitors

Active Org.

The University of Tokushima

Originator Org.

The University of Tokushima

Active Indication

Neoplasms

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with NHE5

100 Translational Medicine associated with NHE5

0 Patents (Medical) associated with NHE5

Literatures (Medical) associated with NHE5

01 Aug 2024·Journal of Biological Chemistry

GGA1 interacts with the endosomal Na+/H+ exchanger NHE6 governing localization to the endosome compartment

Article

Author: Morrow, Eric M ; Ouyang, Qing ; Ma, Li ; Schmidt, Michael ; Kasula, Ravi Kiran

Mutations in the endosomal Na+/H+ exchanger 6 (NHE6) cause Christianson syndrome, an X-linked neurological disorder. NHE6 functions in regulation of endosome acidification and maturation in neurons. Using yeast two-hybrid screening with the NHE6 carboxyl terminus as bait, we identify Golgi-associated, gamma adaptin ear-containing, ADP-ribosylation factor (ARF) binding protein 1 (GGA1) as an interacting partner for NHE6. We corroborated the NHE6-GGA1 interaction using: coimmunoprecipitation; overexpressed constructs in mammalian cells; and coimmunoprecipitation of endogenously expressed GGA1 and NHE6 from neuroblastoma cells, as well as from the mouse brain. We demonstrate that GGA1 interacts with organellar NHEs (NHE6, NHE7, and NHE9) and that there is significantly less interaction with cell-surface localized NHEs (NHE1 and NHE5). By constructing hybrid NHE1/NHE6 exchangers, we demonstrate the cytoplasmic tail of NHE6 interacts most strongly with GGA1. We demonstrate the colocalization of NHE6 and GGA1 in cultured, primary hippocampal neurons, using super-resolution microscopy. We test the hypothesis that the interaction of NHE6 and GGA1 functions in the localization of NHE6 to the endosome compartment. Using subcellular fractionation experiments, we show that NHE6 is mislocalized in GGA1 KO cells, wherein we find less NHE6 in endosomes, but more NHE6 transport to lysosomes, and more Golgi retention of NHE6, with increased exocytosis to the surface plasma membrane. Consistent with NHE6 mislocalization, and Golgi retention, we find the intraluminal pH in Golgi to be alkalinized in GGA1-null cells. Our study demonstrates a new interaction between NHE6 and GGA1 which functions in the localization of this intracellular NHE to the endosome compartment.

01 Feb 2024·Bioorganic & Medicinal Chemistry

Development of UTX-143, a selective sodium-hydrogen exchange subtype 5 inhibitor, using amiloride as a lead compound

Article

Author: Terashima, Minoru ; Shinohara, Yusei ; Suzuki, Takeshi ; Ninomiya, Itasu ; Endo, Yoshio ; Uto, Yoshihiro ; Yamada, Hisatsugu ; Takino, Takahisa ; Morimoto, Kashin ; Komiya, Yuki

NHE5, an isoform of the Na⁺/H⁺ exchanger (NHE) protein, is an ion-transporting membrane protein that regulates intracellular pH and is highly expressed in colorectal adenocarcinoma. Therefore, we hypothesized that NHE5 inhibitors can be used as anticancer drugs. However, because NHE1 is ubiquitously expressed in all cells, it is extremely important to demonstrate its selective inhibitory activity against NHE5. We used amiloride, an NHE non-selective inhibitor, as a lead compound and created UTX-143, which has NHE5-selective inhibitory activity, using a structure-activity relationship approach. UTX-143 showed selective cytotoxic effects on cancer cells and reduced the migratory and invasive abilities of cancer cells. These results suggest a new concept wherein drugs exhibit cancer-specific cytotoxic effects through selective inhibition of NHE5 and the possibility of UTX-143 as a lead NHE5-selective inhibitor.

01 Sep 2023·Experimental cell research

SLC9A5 promotes tumor growth and cell motility via ACOX1-mediated peroxisomal fatty acid oxidation.

Article

Author: Zheng, Ruipan ; Wang, Yurong

Growing evidence suggests a strong association between decreased lipid catabolism and the development of cancer. Solute carrier family 9 member A5 (SLC9A5) plays a regulatory role in colorectal function. However, the specific involvement of SLC9A5 in colorectal cancer (CRC) remains unclear, as well as its potential connection to lipid catabolism. We found that SLC9A5 exhibited significantly higher expression in CRC tumor tissues compared to adjacent paratumor tissues, as confirmed through analysis of the TCGA database and validation on a CRC tissue chip using IHC. Furthermore, in vitro experiments showed that knockdown of SLC9A5 resulted in suppressed cell proliferation, migration, and invasion. Then we performed bioinformatics analysis and found that SLC9A5 was significantly enriched in peroxisomal fatty acid oxidation (FAO) pathway and negatively correlated with its first rate-limiting enzyme acyl-CoA oxidases (ACOX). Interestingly, the expression of ACOX1, as well as FAO process indicated by changes in very long chain fatty acid levels, were enhanced upon SLC9A5 knockdown in CRC cells. Moreover, the attenuated tumor growth, migration, invasion, and increased FAO observed after SLC9A5 knockdown could be reversed by simultaneous knockdown of both SLC9A5 and ACOX1. In summary, these findings reveal the oncogenic role of SLC9A5 in CRC, particularly in relation to ACOX1-mediated peroxidation, and might serve as a promising therapeutic target for inhibiting the progression of colorectal cancer.

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