Acid-sensing ion channels: dual function proteins for chemo-sensing and mechano-sensing

Abstract

Background: Acid-sensing ion channels (ASICs) are a group of amiloride-sensitive ligand-gated ion channels belonging to the family of degenerin/epithelial sodium channels. ASICs are predominantly expressed in both the peripheral and central nervous system and have been characterized as potent proton sensors to detect extracellular acidification in the periphery and brain.

Main body: Here we review the recent studies focusing on the physiological roles of ASICs in the nervous system. As the major acid-sensing membrane proteins in the nervous system, ASICs detect tissue acidosis occurring at tissue injury, inflammation, ischemia, stroke, and tumors as well as fatiguing muscle to activate pain-sensing nerves in the periphery and transmit pain signals to the brain. Arachidonic acid and lysophosphocholine have been identified as endogenous non-proton ligands activating ASICs in a neutral pH environment. On the other hand, ASICs are found involved in the tether model mechanotransduction, in which the extracellular matrix and cytoplasmic cytoskeletons act like a gating-spring to tether the mechanically activated ion channels and thus transmit the stimulus force to the channels. Accordingly, accumulating evidence has shown ASICs play important roles in mechanotransduction of proprioceptors, mechanoreceptors and nociceptors to monitor the homoeostatic status of muscle contraction, blood volume, and blood pressure as well as pain stimuli.

Conclusion: Together, ASICs are dual-function proteins for both chemosensation and mechanosensation involved in monitoring physiological homoeostasis and pathological signals.

Keywords: ASIC; ASIC3; Mechanotransduction; Nociceptor; Pain; Proprioception.

Fig. 1

ASICs localize in a variety of somatosensory nerve terminals responsible for both chemo-sensing and mechano-sensing functions. In skin, ASICs are expressed in the free nerve endings of nociceptors and cutaneous nerves projecting to specialized mechanoreceptors such as Meissner corpuscles, Ruffini corpuscles, Pacinian corpuscles, hair follicles, and Merkel cells. In muscle, ASICs are expressed in the free nerve endings of nociceptors and group Ia muscle spindle nerve fibers in the intrafusal bag. In the cardiovascular system, ASICs are expressed in cardiac sensory nerves and baroreceptors. In the gut, ASICs are expressed in many subpopulations of gastrointestinal afferents. In the spinal cord, ASIC-expressing sensory afferents innervate to distinct dorsal horn laminae corresponding to their specific sensory perception

Fig. 2

The structure and function of ASICs. a A trimeric ASIC channel comprises three subunits. Each subunit constructs “a hand holding a ball” structure to sense the extracellular proton and regulate the proton-gated currents. There are three major categories of non-proton regulators (synthetic/nature compound, endogenous metabolites, and divalent cations) to activate or modulate ASICs in a conformational change of structure. b The ASIC1a (or ASIC1b, ASIC2a) homomeric channel mediates a transient current, whereas the ASIC3 homomeric channel mediates a biphasic current containing a transient component followed by a non-inactivated sustained component. c, d The non-proton regulators (e.g., 1 mM GMQ) may shift the activation (open circle) or inactivation (filled circle) curve by changing the conformation of ASIC channels and enhance the window current (the shadow region underneath the dotted lines)

Fig. 3

The molecular apparatus that mediates the “tether model” mechanotransduction is conserved between nematodes and mammals. a Caenorhabditis elegans has many mechanosensory abnormality (mec) mutant genes involved in the tether-model mechanotransduction responsible for gentle touch. These mec gene products are MEC-4 and MEC-10 (DEG/ENaC channels), MEC-2 and MEC-6 (channel-associated proteins), MEC-7 and MEC-12 (protofilament microtubules), and MEC-1, MEC-5, and MEC-9 (extracellular matrix proteins). These proteins illustrate a tethering gating model of mechanically activated ion channels in nematodes. b In mammals, ASICs are homologs of MEC-4 and MEC-10 and are also involved in the tether model of mechanotransduction. ASICs interact with channel-associated proteins PICK1 and STOML3 (and possibly whirlin) and could be regulated by extracellular matrix proteins (e.g., collagen, laminin, and fibronectin) or cytoskeleton proteins such as actin and microtubules

Fig. 4

Approaches and mechano-gating mechanisms of the “bilayer model” and “tether model” of mechanically activated ion channels. a Direct neurite indentation by using a blunt pipette alters membrane tension and thus opens the mechanically activated ion channel of the bilayer model (e.g., PIEZO2). b Substrate deformation-driven neurite stretch acts on channel-tethering proteins of the extracellular matrix and cytoskeletons and thus opens the mechanically activated ion channels of the tether model (e.g., MEC-4/MEC-10 or ASICs)