Acid-sensing ion channels (ASICs) as pharmacological targets for neurodegenerative diseases

Abstract

A significant drop of tissue pH or acidosis is a common feature of acute neurological conditions such as ischemic stroke, brain trauma, and epileptic seizures. Acid-sensing ion channels, or ASICs, are proton-gated cation channels widely expressed in peripheral sensory neurons and in the neurons of the central nervous system. Recent studies have demonstrated that activation of these channels by protons plays an important role in a variety of physiological and pathological processes such as nociception, mechanosensation, synaptic plasticity, and acidosis-mediated neuronal injury. This review provides an overview of the recent advance in electrophysiological, pharmacological characterization of ASICs, and their role in neurological diseases. Therapeutic potential of current available ASIC inhibitors is discussed.

Figure 1

Proposed tetrameric structure of ASICs. Each channel is assembled by 4 identical or different subunits. Each subunit consists of two transmembrane domain (I & II) linked by large cycteine rich extracellular domain with intracellular N- and C- termini. For homomeric ASIC1a channels, activation of the channels by H⁺ binding induces entry of Na⁺ and Ca²⁺ ions.

Figure 2

Chemical structure of amiloride and A-317567.

Figure 3

Amino acid sequence and disulfide linkage for PcTX1 and APETx2.

Figure 4

Simplified diagram demonstrating the role of ASIC1a activation in ischemic neuronal injury and the neuroprotection by ASIC1a blocker/inhibitor. Upper left panel represents neurons in ischemic conditions where the concentration of extracellullar protons is high. Binding of protons opens the channels resulting in large influx of Na⁺ and Ca²⁺ ions. Overloading neurons with Ca²⁺ induces neuronal injury and large infarct volume of the brain (upper right panel). Lower left panel represents neurons in ischemic conditions but in the presence of ASIC blocker or inhibitor. Influx of Na⁺ and Ca²⁺ ions are reduced due to a direct blockade of the channel (e.g. by amiloride) or an alteration of channel gating (e.g. by PcTX1), resulting in neuroprotection and small infarct volume (lower right panel).