Emerging roles of Na+/H+ exchangers in epilepsy and developmental brain disorders. (March 2016)

• Record Type: Journal Article
• Authors: Zhao, Hanshu; Carney, Karen E.; Falgoust, Lindsay; Pan, Jullie W.; Sun, Dandan; Zhang, Zhongling
• Is Part Of: Progress in neurobiology. Volume 138/139/140(2016:Mar.)
• Page Start: 19
• Page End: 35
• Publication Date: 2016-03
• Subjects: CNS central nervous system -- NHE Na+/H+ exchanger -- ADHD attention deficit hyperactivity disorder -- CA carbonic anhydrase -- pHi intracellular pH -- pHo extracellular pH -- BBB blood–brain barrier -- pCO2 partial pressure of carbon dioxide -- V-ATPase vacuolar-type H+ ATPase -- Swe slow-wave epilepsy -- ECoG electrocorticographic -- XLID X-chromosome linked intellectual disability -- ID intellectual disability -- CS Christianson syndrome -- CaM calmodulin -- CHP calcineurin homologous protein -- ASD autism spectrum disorder -- GABA γ-aminobutyric acid -- GABAR γ-aminobutyric acid receptor -- GABAT GABA transaminase -- GAT GABA transporter -- AED antiepileptic drug -- NBC sodium-coupled bicarbonate transporter -- AE anion exchanger -- KO knockout -- PMCAs Ca2+/H+ ATPases -- DIA depolarization-induced alkalization -- PTZ pentylenetetrazole -- MCT monocarboxylate transporter -- RACK1 receptor for activated C-kinase -- XLMR X-linked mental retardation; ADHD -- Autism -- Excitability -- NHE1 -- NHE6 -- NHE9; Neurobiology -- Periodicals; Neurology -- Periodicals; Neurology -- Periodicals; Neurobiologie -- Périodiques; 612.8
• DOI: 10.1016/j.pneurobio.2016.02.002
• Languages: English
• ISSNs: 0301-0082

Abstract

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.