Last update 19 Sep 2024

NHE5

Last update 19 Sep 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.

07 Oct 2023·International journal of molecular sciences

Na⁺/H⁺ Exchangers (NHEs) in Mammalian Sperm: Essential Contributors to Male Fertility.

Review

Author: Gardner, Cameron C ; James, Paul F

Na⁺/H⁺ exchangers (NHEs) are known to be important regulators of pH in multiple intracellular compartments of eukaryotic cells. Sperm function is especially dependent on changes in pH and thus it has been postulated that NHEs play important roles in regulating the intracellular pH of these cells. For example, in order to achieve fertilization, mature sperm must maintain a basal pH in the male reproductive tract and then alkalize in response to specific signals in the female reproductive tract during the capacitation process. Eight NHE isoforms are expressed in mammalian testis/sperm: NHE1, NHE3, NHE5, NHE8, NHA1, NHA2, NHE10, and NHE11. These NHE isoforms are expressed at varying times during spermatogenesis and localize to different subcellular structures in developing and mature sperm where they contribute to multiple aspects of sperm physiology and male fertility including proper sperm development/morphogenesis, motility, capacitation, and the acrosome reaction. Previous work has provided evidence for NHE3, NHE8, NHA1, NHA2, and NHE10 being critical for male fertility in mice and NHE10 has recently been shown to be essential for male fertility in humans. In this article we review what is known about each NHE isoform expressed in mammalian sperm and discuss the physiological significance of each NHE isoform with respect to male fertility.

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