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.

Proton-mediated Conformational Changes in an Acid-sensing Ion Channel

“…These proteins are important pharmacological targets, as they participate in various sensorial pathways, including nociception, synaptic transmission, and the physiopathology of ischemic stroke (3)(4)(5). Functional experiments have identified at least three distinct states: closed resting, open channel, and desensitized.…”

Acid-Sensing Ion Channels in Neurodegenerative Diseases: Potential Therapeutic Target

“…Moreover, ASIC1a channels play critical roles in neurodegenerative diseases such as multiple sclerosis (Friese et al, 2007;Vergo et al, 2011), Parkinson's (Arias et al, 2008) and Huntington's (Wong et al, 2008) disease and in seizures (Chang et al, 2007;Ziemann et al, 2008) and depression . Thus, controlling their activation might ameliorate acidosismediated CNS disorders (Xiong et al, 2008). This chapter provides an overview of recent advance in electrophysiological properties as well as pharmacological profiles of ASICs, and their roles in neurodegenerative disorders.…”

“…Acidosis can activate a distinct family of ion channels: acid-sensing ion channels (ASICs) (Waldmann et al, 1997b), which are heavily expressed in the peripheral sensory and central neurons Krishtal, 2003;Wemmie et al, 2006;Lingueglia, 2007;Xiong et al, 2006Xiong et al, , 2007Xiong et al, , 2008. ASICs belong to the amiloride-sensitive degenerin/epithelial Na + channel (DEG/ENaC) superfamily (Kellenberger & Schild, 2002).…”

Acid Sensing Ion Channels (Asics): Potential Targets for the Discovery of Novel Therapeutics in Disease Management

“…ASICs have been de ec ed hroughou he nervous sys em, specifically in areas of high synaptic densi y, localizing primarily o he soma and processes of neurons [18][19]. Their expression pattern has sugges ed ha hese channels play a role in sensory perception and various neural processes [20][21]. ASICs have widespread dis ribution o many regions in he nervous sys em including dorsal roo ganglia, cor ex, hippocampus, basal ganglia, amygdale, olfac ory bulb, cerebrum and elsewhere [22 -24].…”

“…A s rong ASIC-media ed depolarization, however, can inhibi an already actively signaling neuron. ASIC1a has a small permeabili y for Ca2+ in addition o i s Na+ permeabili y, and some of i s cellular functions, as for example neurodegeneration after ischem-ic s roke are hough o depend on a Ca2+ en ry in o he cell [31][32][33][34][35][36]. Expression pattern of ASIC subuni s in differen cells and tissue ypes of functional organization are represen ed in Table 1.…”