ASIC3 channels in multimodal sensory perception

Abstract

Acid-sensing ion channels (ASICs), which are members of the sodium-selective cation channels belonging to the epithelial sodium channel/degenerin (ENaC/DEG) family, act as membrane-bound receptors for extracellular protons as well as nonproton ligands. At least five ASIC subunits have been identified in mammalian neurons, which form both homotrimeric and heterotrimeric channels. The highly proton sensitive ASIC3 channels are predominantly distributed in peripheral sensory neurons, correlating with their roles in multimodal sensory perception, including nociception, mechanosensation, and chemosensation. Different from other ASIC subunit composing ion channels, ASIC3 channels can mediate a sustained window current in response to mild extracellular acidosis (pH 7.3-6.7), which often occurs accompanied by many sensory stimuli. Furthermore, recent evidence indicates that the sustained component of ASIC3 currents can be enhanced by nonproton ligands including the endogenous metabolite agmatine. In this review, we first summarize the growing body of evidence for the involvement of ASIC3 channels in multimodal sensory perception and then discuss the potential mechanisms underlying ASIC3 activation and mediation of sensory perception, with a special emphasis on its role in nociception. We conclude that ASIC3 activation and modulation by diverse sensory stimuli represent a new avenue for understanding the role of ASIC3 channels in sensory perception. Furthermore, the emerging implications of ASIC3 channels in multiple sensory dysfunctions including nociception allow the development of new pharmacotherapy.

Keywords: ASIC3; Acid-sensing ion channel; chemosensation; mechanosensation; nociception; nonproton ligand.

Figure 1

Distribution of ASIC3 in peripheral tissues and its potential roles. In addition to its well-known roles in DRG neurons (see the text), ASIC3 has an unexpected widespread expression in a variety of non-neuronal tissues as indicated.

Figure 2

Structure and activation modes of ASIC3. The structural model of ASIC3, shown parallel to the membrane layer, is a homologue model based on the X-ray crystal structure of ASIC1 (chicken, PDB code: 2QTS) (7). One ASIC3 subunit is shown in cartoon view, while the other two ASIC1 subunits are shown in line view or surface view. As a proton-gated ion channel, ASIC3 channels manifest different kinds of channel activation, shown with different scale and kinetics, in response to extracellular acidosis. Mild acidosis (i.e., pH 7.0) induces a considerable peak current followed by a slow desensitizing current (panel a). Extreme acidosis (i.e., pH 5.0) induces a larger peak current (panel b) and a much smaller sustained current (panel c). In addition to acid-induced channel activation, nonproton ligands (i.e., GMQ) induce a sustained current (panel d) at physiologically normal pH (pH 7.4) (13). The arrow highlights the nonproton ligand sensor domain lined by residues around E423 and E79 of the extracellular palm domain of the ASIC3 channel (13). Different modes of ASIC3 activation may correspond to different sensory perception roles (see the text). The typical current traces show differential kinetics of channel activation responding to protons and GMQ, respectively. Note the scale difference of the current amplitude.

Figure 3

ASIC3-dependent nociceptive signaling pathway during inflammation. ASIC3 is expressed in nociceptors, which respond to many pro-inflammatory mediators, such as acidosis (H⁺), serotonin (5-HT), arachidonic acid (AA), bradykinin (BK), prostaglandin E2 (PGE2), nerve growth factor (NGF), and agmatine (AGM). Both H⁺ and AGM induce ASIC3 channel activation independently, although they are mutually interacting. AA and hyperosmolarity (H-Osm) indirectly facilitate ASIC3 activation. 5-HT, BK, PGE2, and NGF stimulate ASIC3 expression. The multicolor DRG neurons represent diverse sensory pathways relaying various nociceptive inputs dependent on ASIC3 channels to the spinal dorsal horn (SDH) under inflammation, although the exact distribution profiles of ASIC3 in nerve fibers are unclear. Stimulation of the nociceptor triggers a synaptic response in the SDH, and the noxious stimuli are then transmitted to the supraspinal structures as indicated.