Increases in extracellular
proton concentrations, which takes place in physiological conditions such as synaptic signaling and pathological conditions such as tissue
inflammation,
ischemic stroke,
traumatic brain injury, and epileptic seizure, activates a unique family of membrane
ion channels; the
acid-sensing ion channels (ASICs). All ASICs belong to
amiloride-sensitive
degenerin/epithelial Na(+) channel superfamily. Four genes encoded at seven sub-units have been identified. ASICs are expressed primarily in neurons and have been shown to play critical roles in synaptic plasticity, learning/memory, fear conditioning, sensory transduction, pain perception, ischemic
brain injury, seizure, and other neurological as well as psychological disorders. Although
protons are the primary activator for ASICs, the properties and/or level of expression of these channels are modulated dramatically by
neuropeptides, di-and polyvalent
cations, inflammatory mediators, associated
proteins, and
protein phosphorylations, etc. Modulation of ASICs can result in profound changes in the activities and functions of these channels in both physiological and
pathological processes. In this article, we provide an up to date review on the modulations of ASICs by exogenous agents and endogenous signaling molecules. A better understanding of how ASICs can be modulated should help define new strategies to counteract the deleterious effects of dysregulated ASIC activity.