title: Emerging roles of Na⁺/H⁺ exchangers in epilepsy and developmental brain disorders.
abstract: 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. Altering NHE function significantly influences neuronal excitability and plays a role in epilepsy. This review gives an overview of pH regulatory mechanisms in the brain with a special focus on the NHE family and the relationship between epilepsy and dysfunction of NHE isoforms. We first discuss how cells translocate acids and bases across the membrane and establish pH homeostasis as a result of the concerted effort of enzymes and ion transporters. We focus on the specific roles of the NHE family by detailing how the loss of NHE1 in two NHE mutant mice results in enhanced neuronal excitability in these animals. Furthermore, we highlight new findings on the link between mutations of NHE6 and NHE9 and developmental brain disorders including epilepsy, autism, and attention deficit hyperactivity disorder (ADHD). These studies demonstrate the importance of NHE proteins in maintaining H(+) homeostasis and their intricate roles in the regulation of neuronal function. A better understanding of the mechanisms underlying NHE1, 6, and 9 dysfunctions in epilepsy formation may advance the development of new epilepsy treatment strategies.
authors.affiliation: Department of Neurology, The First Affiliated Hospital of the Harbin Medical University, Harbin, China.|Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15213, USA.
authors.forename: Hanshu
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15213, USA.
authors.forename: Karen E
authors.initials: KE
authors.lastname: Carney
authors.affiliation: Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15213, USA.
authors.forename: Lindsay
authors.initials: L
authors.lastname: Falgoust
authors.affiliation: Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15213, USA.
authors.forename: Jullie W
authors.initials: JW
authors.lastname: Pan
authors.affiliation: Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15213, USA.|Veterans Affairs Pittsburgh Health Care System, Geriatric Research, Educational and Clinical Center, Pittsburgh, PA 15213, USA.
authors.forename: Dandan
authors.initials: D
authors.lastname: Sun
authors.affiliation: Department of Neurology, The First Affiliated Hospital of the Harbin Medical University, Harbin, China.
authors.forename: Zhongling
authors.initials: Z
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001289:Attention Deficit Disorder with Hyperactivity / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D001321:Autistic Disorder / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D004827:Epilepsy / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D017923:Sodium-Hydrogen Exchangers
keywords: ADHD; Autism; Excitability; NHE1; NHE6; NHE9