Physiological and pathological functions of acid-sensing ion channels in the central nervous system

Abstract

Protons are important signals for neuronal function. In the central nervous system (CNS), proton concentrations change locally when synaptic vesicles release their acidic contents into the synaptic cleft, and globally in ischemia, seizures, traumatic brain injury, and other neurological disorders due to lactic acid accumulation. The finding that protons gate a distinct family of ion channels, the acid-sensing ion channels (ASICs), has shed new light on the mechanism of acid signaling and acidosis-associated neuronal injury. Accumulating evidence has suggested that ASICs play important roles in physiological processes such as synaptic plasticity, learning/memory, fear conditioning, and retinal integrity, and in pathological conditions such as brain ischemia, multiple sclerosis, epileptic seizures, and malignant glioma. Thus, targeting these channels may lead to novel therapeutic interventions for neurological disorders. The goal of this review is to provide an update on recent advances in our understanding of the functions of ASICs in the CNS.

Figure 1

Proposed structure for homomeric ASIC1a channels. A. Functional homomeric ASIC1a channels are formed by trimeric assembly of three identical subunits. Binding of protons opens the channel allowing flux of Na⁺ and Ca²⁺ ions into the cell. B. Top view of an open and closed channel.