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Julie C Ullman, Jing Yang, Michael Sullivan, Jacob Bendor, Jonathan Levy, Ellen Pham, Katlin Silm, Helia Seifikar, Vikaas S Sohal, Roger A Nicoll, Robert H Edwards
Psychoactive compounds such as chloroquine and amphetamine act by dissipating the pH gradient across intracellular membranes, but the physiological mechanisms that normally regulate organelle pH remain poorly understood. Interestingly, recent human genetic studies have implicated the endosomal Na+ /H+ exchanger NHE9 in both autism spectrum disorders (ASD) and attention deficit hyperactivity disorder (ADHD). Plasma membrane NHEs regulate cytosolic pH, but the role of intracellular isoforms has remained unclear...
January 23, 2018: Nature Communications
Mahmoud Abdul Karim, Christopher Leonard Brett
Loss-of-function mutations in human endosomal Na+ (K+ )/H+ exchangers (NHEs) NHE6 and NHE9 are implicated in neurological disorders including Christianson syndrome, autism, and attention deficit and hyperactivity disorder. These mutations disrupt retention of surface receptors within neurons and glial cells by affecting their delivery to lysosomes for degradation. However, the molecular basis of how these endosomal NHEs control endocytic trafficking is unclear. Using Saccharomyces cerevisiae as a model, we conducted cell-free organelle fusion assays to show that transport activity of the orthologous endosomal NHE Nhx1 is important for multivesicular body (MVB)-vacuolar lysosome fusion, the last step of endocytosis required for surface protein degradation...
February 1, 2018: Molecular Biology of the Cell
Hari Prasad, James Osei-Owusu, Rajini Rao
Na(+)/H(+) exchanger isoform 9, NHE9, finely tunes the pH within the endosomal lumen to regulate cargo trafficking and turnover. In patients with autism, genetic approaches have revealed deletions, truncations and missense mutations in the gene encoding NHE9 (SLC9A9). To help establish causality, functional evaluation is needed to distinguish pathogenic mutations from harmless polymorphisms. Here, we evaluated three previously uncharacterized NHE9 variants, P117T, D496N, and Q609K reported in patients with autism and epilepsy...
April 2017: Matters
Rami Beydoun, Mohamed A Hamood, Daniela M Gomez Zubieta, Kalyan C Kondapalli
Iron is essential for brain function, with loss of iron homeostasis in the brain linked to neurological diseases ranging from rare syndromes to more common disorders, such as Parkinson's and Alzheimer's diseases. Iron entry into the brain is regulated by the blood-brain barrier (BBB). Molecular mechanisms regulating this transport are poorly understood. Using an in vitro model of the BBB, we identify NHE9, an endosomal cation/proton exchanger, as a novel regulator of this system. Human brain microvascular endothelial cells (hBMVECs) that constitute the BBB receive brain iron status information via paracrine signals from ensheathing astrocytes...
March 10, 2017: Journal of Biological Chemistry
Meeta Cardon, Karen D Evankovich, J Lloyd Holder
Genes encoding proteins critical for intracellular vesicular transport are an emerging area of importance for neurologists. In particular, proteins that create and maintain the correct compartmental pH, such as the endosomal Na(+)/H(+) exchangers (NHEs), have been implicated in a wide range of human diseases, including cardiovascular, inflammatory bowel, renal, and neurologic disorders, which demonstrates the critical cellular function of these proteins.(1-3) Two NHEs, NHE6 and NHE9, have been linked to neurologic disorders in children...
April 2016: Neurology. Genetics
Hanshu Zhao, Karen E Carney, Lindsay Falgoust, Jullie W Pan, Dandan Sun, Zhongling Zhang
Epilepsy is a common central nervous system (CNS) disease characterized by recurrent transient neurological events occurring due to abnormally excessive or synchronous neuronal activity in the brain. The CNS is affected by systemic acid-base disorders, and epileptic seizures are sensitive indicators of underlying imbalances in cellular pH regulation. Na(+)/H(+) exchangers (NHEs) are a family of membrane transporter proteins actively involved in regulating intracellular and organellar pH by extruding H(+) in exchange for Na(+) influx...
March 2016: Progress in Neurobiology
Etana Padan, Meytal Landau
The transmembranal Na(+)/H(+) antiporters transport sodium (or several other monovalent cations) in exchange for H(+) across lipid bilayers in all kingdoms of life. They are critical in pH homeostasis of the cytoplasm and/or organelles. A particularly notable example is the SLC9 gene family, which encodes Na(+)/H(+) exchangers (NHEs) in many species from prokaryotes to eukaryotes. In humans, these proteins are associated with the pathophysiology of various diseases. Yet, the most extensively studied Na(+)/H(+) antiporter is Ec-NhaA, the main Na(+)/H(+) antiporter of Escherichia coli...
2016: Metal Ions in Life Sciences
Junying Chen, Hong Yang, Jing Wen, Kongjia Luo, Qianwen Liu, Yijie Huang, Yuzhen Zheng, Zihui Tan, Qingyuan Huang, Jianhua Fu
Recently, we found that NHE9 mRNA was upregulated in chemoradiotherapy (CRT)-resistant esophageal squamous cell carcinoma (ESCC); however, the underlying mechanisms were unclear. Here, we aimed to clarify the functional contribution of NHE9 to CRT resistance, understand the molecular basis of NHE9-dependent resistance in ESCC, and identify potential therapeutic targets. Our results showed that NHE9 prevented CRT-induced apoptosis. Importantly, we found that RACK1 is a novel binding partner of NHE9 and that NHE9-dependent induction of CRT resistance requires the activation of RACK1-associated Src/Akt/β-catenin signaling...
May 20, 2015: Oncotarget
Kalyan C Kondapalli, Jose P Llongueras, Vivian Capilla-González, Hari Prasad, Anniesha Hack, Christopher Smith, Hugo Guerrero-Cázares, Alfredo Quiñones-Hinojosa, Rajini Rao
Epidermal growth factor receptor (EGFR) signalling is a potent driver of glioblastoma, a malignant and lethal form of brain cancer. Disappointingly, inhibitors targeting receptor tyrosine kinase activity are not clinically effective and EGFR persists on the plasma membrane to maintain tumour growth and invasiveness. Here we show that endolysosomal pH is critical for receptor sorting and turnover. By functioning as a leak pathway for protons, the Na(+)/H(+) exchanger NHE9 limits luminal acidification to circumvent EGFR turnover and prolong downstream signalling pathways that drive tumour growth and migration...
2015: Nature Communications
Kalyan C Kondapalli, Hari Prasad, Rajini Rao
Autism imposes a major impediment to childhood development and a huge emotional and financial burden on society. In recent years, there has been rapidly accumulating genetic evidence that links the eNHE, a subset of Na(+)/H(+) exchangers that localize to intracellular vesicles, to a variety of neurological conditions including autism, attention deficit hyperactivity disorder (ADHD), intellectual disability, and epilepsy. By providing a leak pathway for protons pumped by the V-ATPase, eNHE determine luminal pH and regulate cation (Na(+), K(+)) content in early and recycling endosomal compartments...
2014: Frontiers in Cellular Neuroscience
Nina Milosavljevic, Michaël Monet, Isabelle Léna, Frédéric Brau, Sandra Lacas-Gervais, Sylvain Feliciangeli, Laurent Counillon, Mallorie Poët
Vesicular H(+)-ATPases and ClC-chloride transporters are described to acidify intracellular compartments, which also express the highly conserved Na(+)/H(+) exchangers NHE6, NHE7, and NHE9. Mutations of these exchangers cause autism-spectrum disorders and neurodegeneration. NHE6, NHE7, and NHE9 are hypothesized to exchange cytosolic K(+) for H(+) and alkalinize vesicles, but this notion has remained untested in K(+) because their intracellular localization prevents functional measurements. Using proton-killing techniques, we selected a cell line that expresses wild-type NHE7 at the plasma membrane, enabling measurement of the exchanger's transport parameters...
May 8, 2014: Cell Reports
Daniel G Fuster, R Todd Alexander
The SLC9 gene family encodes Na(+)/H(+) exchangers (NHEs). These transmembrane proteins transport ions across lipid bilayers in a diverse array of species from prokaryotes to eukaryotes, including plants, fungi, and animals. They utilize the electrochemical gradient of one ion to transport another ion against its electrochemical gradient. Currently, 13 evolutionarily conserved NHE isoforms are known in mammals [22, 46, 128]. The SLC9 gene family (solute carrier classification of transporters: www.bioparadigms...
January 2014: Pflügers Archiv: European Journal of Physiology
Stephen V Faraone, Yanli Zhang-James
Medications for attention deficit hyperactivity disorder (ADHD) are only partially effective. Ideally, new treatment targets would derive from a known pathophysiology. Such data are not available for ADHD. We combine evidence for new etiologic pathways with bioinformatics data to assess the possibility that existing drugs might be repositioning for treating ADHD. We use this approach to determine if prior data implicating the sodium/hydrogen exchanger 9 gene (SLC9A9) in ADHD implicate sodium/hydrogen exchange (NHE) inhibitors as potential treatments...
October 2013: American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics
Kalyan C Kondapalli, Anniesha Hack, Maya Schushan, Meytal Landau, Nir Ben-Tal, Rajini Rao
NHE9 (SLC9A9) is an endosomal cation/proton antiporter with orthologues in yeast and bacteria. Rare, missense substitutions in NHE9 are genetically linked with autism but have not been functionally evaluated. Here we use evolutionary conservation analysis to build a model structure of NHE9 based on the crystal structure of bacterial NhaA and use it to screen autism-associated variants in the human population first by phenotype complementation in yeast, followed by functional analysis in primary cortical astrocytes from mouse...
2013: Nature Communications
M Schwede, K Garbett, K Mirnics, D H Geschwind, E M Morrow
No abstract text is available yet for this article.
March 2014: Molecular Psychiatry
Yanli Zhang-James, Frank A Middleton, Terje Sagvolden, Stephen V Faraone
SLC9A9 [solute carrier family 9, member 9, also known as Na(+)/H(+) exchanger member 9 (NHE9)], has been implicated in human attention deficit/hyperactivity disorder (ADHD), autism, and rat studies of hyperactivity and inattentiveness. SLC9A9 is a membrane protein that regulates the luminal pH of the recycling endosome. We recently reported the interactions of SLC9A9 with two molecules: calcineurin homologous protein (CHP) and receptor for activated C-kinase 1 (RACK1). We also reported two novel SLC9A9 mutations and abnormal gene expression profiles in the brains of an inattentive type rat model of ADHD (WKY/NCrl rat)...
2012: Developmental Neuroscience
Ichiro Onishi, Paulo J C Lin, Yuka Numata, Pamela Austin, Jane Cipollone, Michel Roberge, Calvin D Roskelley, Masayuki Numata
Na+/H+ exchangers (NHEs) are a group of secondary active antiporters that regulate cellular pH, cell volume and ion homeostasis. In humans, nine isoforms (NHE1-NHE9) were identified and characterized as functional NHEs. While a growing body of evidence indicates that NHE1 generates an acidic tumor environment and thereby contributes to tumor invasion, little is known about the role of other NHE isoforms in tumor progression. NHE7 is a unique member of the NHE gene family that dynamically shuttles between the trans-Golgi network, endosomes and the plasma membrane, and regulates the luminal pH of these organelles...
February 2012: Oncology Reports
Yanli Zhang-James, Tania DasBanerjee, Terje Sagvolden, Frank A Middleton, Stephen V Faraone
SLC9A9 (solute carrier family 9, member 9, also known as Na+/H+ exchanger member (NHE9)) is a membrane protein that regulates the luminal pH of the recycling endosome, an essential organelle for synaptic transmission and plasticity. SLC9A9 has been implicated in human attention deficit hyperactivity disorder (ADHD) and in rat studies of hyperactivity. We examined the SLC9A9 gene sequence and expression profile in prefrontal cortex, dorsal striatum and hippocampus in two genetic rat models of ADHD. We report two mutations in a rat model of inattentive ADHD, the WKY/NCrl rat, which affect the interaction of SLC9A9 with calcineurin homologous protein (CHP)...
December 2011: American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics
Yuka Yasuda, Ryota Hashimoto, Hidenaga Yamamori, Kazutaka Ohi, Motoyuki Fukumoto, Satomi Umeda-Yano, Ikuko Mohri, Akira Ito, Masako Taniike, Masatoshi Takeda
BACKGROUND: The autism spectrum disorders (ASDs) are complex neurodevelopmental disorders that result in severe and pervasive impairment in the development of reciprocal social interaction and verbal and nonverbal communication skills. In addition, individuals with ASD have stereotypical behavior, interests and activities. Rare mutations of some genes, such as neuroligin (NLGN) 3/4, neurexin (NRXN) 1, SHANK3, MeCP2 and NHE9, have been reported to be associated with ASD. In the present study, we investigated whether alterations in mRNA expression levels of these genes could be found in lymphoblastoid cell lines derived from patients with ASD...
2011: Molecular Autism
Dan Mao, Yungen Xu, Xiaoping Hu, Guomin Zhang, Jin Dong, Guoqing Gong
The Na(+)/H(+) exchanger (NHE) is a protein expressed in many mammalian cell types. It is involved in intracellular pH (pH(i)) homeostasis by exchanging extracellular Na(+) for intracellular H(+). To date, nine NHE isoforms (NHE1-NHE9) have been identified. NHE1 is the most predominant isoform expressed in mammalian cardiac muscle. A novel series of substituted (quinolinecarbonyl)guanidine derivatives were designed and synthesized as NHE inhibitors. Most compounds can inhibit NHE1-mediated platelet swelling in a concentration-dependent manner, among which compound 7f was the most active and more potent than cariporide...
October 2009: Chemistry & Biodiversity
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