Acid Sensing Ion Channels (ASICs) in the brain: emerging roles in physiology and pathology

While under physiological conditions, extracellular pH in the brain is reasonably constant, several mechanisms induce transient and localized pH fluctuations. Multiple pathologies involve prolonged changes in pH. Therefore, detecting and monitoring pH changes is crucial for the proper functioning of the nervous system. Acid-Sensing Ion Channels (ASICs) are Na+-permeable ion channels, predominantly expressed in the nervous tissue and activated by protons. Thus, ASICs act as pH sensors, leading to neuronal excitation when the pH drops. ASICs belong to the epithelial sodium channel/degenerin (ENaC/DEG) family of amiloride-sensitive transmembrane ion channel proteins. There are at least eight different ASIC subunits encoded by five genes. Functional ASICs assembled in the plasma membrane are homo- or heteromeric trimers. Trimers containing ASIC1a are of particular interest as, in addition to sodium ions, they also conduct calcium ions and thus can regulate multiple cellular processes. ASICs are involved in numerous physiological functions and pathological states. Biophysical properties of ASICs, their evolutionary origins, regulation and pharmacology, their roles in the peripheral nervous system and in the regulation of synaptic transmission have been recently reviewed in many details. Here we shall focus on brain ASICs in the context of the following issues. (i) The role of ASICs in the homeostasis of extracellular рН in the brain; (ii) interactions of ASICs with major neurotransmitters and (iii) ASICs as emerging key factors and drug targets in brain pathology with focus on stroke, neurological consequences of neonatal hyperbilirubinemia, and Alzheimer's disease.