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.

Neuronal hyperactivity causes Na+/H+ exchanger-induced extracellular acidification at active synapses

“…Amongst the other potential mechanisms of extracellular acidification, we focused on the Na + /H + exchangers as several members of this family are known to contribute to the onset and maintenance of epilepsy and other developmental brain disorders (recently reviewed in Zhao et al, 2016). Our data indicate that acidification during ictal activity is mostly due to the Na + /H + exchanger as the addition of the Na + /H + exchanger blocker amiloride strongly reduced the bicuculline-induced synaptic acidification.…”

Selective role of Na+/H+ exchanger in Cx3cr1+ microglial activation, white matter demyelination, and post‐stroke function recovery

“…NHE1 plays an important role in regulating microglial intracellular pH (pH i ) homeostasis, their activation, and migration (Boscia et al, 2016; Liu et al, 2010; Shi et al, 2013; Zhao et al, 2016; Zhu et al, 2016). In particular, NHE1 maintains optimal pH i to support NADPH oxidase (NOX) function during microglial activation (Lam et al, 2013).…”

A direct link between unflavored leptogenesis and low-energy CP violation via the one-loop quantum corrections

“…If one turns to the framework of the minimal supersymmetric standard model (MSSM) extended with the type-I seesaw mechanism, however, the RGE-induced corrections to M D are expected to be much more appreciable. In this MSSM case one may similarly explore a direct connection between unflavored leptogenesis and CP violation at low energies based on the RGE-corrected CI parametrization with O being real [56].…”