Why do neurons sense extracellular acid? In large part, this question has driven increasing investigation on acid-sensing ion channels (ASICs) in the CNS and the peripheral nervous system for the past two decades. Significant progress has been made in understanding the structure and function of ASICs at the molecular level. Studies aimed at clarifying their physiological importance have suggested roles for ASICs in pain, neurological and psychiatric disease. This Review highlights recent findings linking these channels to physiology and disease. In addition, it discusses some of the implications for therapy and points out questions that remain unanswered.

Acid-sensing ion channels in pain and disease

Acid-sensing ion channels (ASICs) are cationic channels activated by extracellular acidosis that are expressed in both central and peripheral nervous systems. Although peripheral ASICs seem to be natural sensors of acidic pain (e.g., in inflammation, ischaemia, lesions or tumours), a direct demonstration is still lacking. We show that ∼60% of rat cutaneous sensory neurons express ASIC3-like currents. Native as well as recombinant ASIC3 respond synergistically to three different inflammatory signals that are slight acidifications (∼pH 7.0), hypertonicity and arachidonic acid (AA). Moderate pH, alone or in combination with hypertonicity and AA, increases nociceptors excitability and produces pain suppressed by the toxin APETx2, a specific blocker of ASIC3. Both APETx2 and the in vivo knockdown of ASIC3 with a specific siRNA also have potent analgesic effects against primary inflammation-induced hyperalgesia in rat. Peripheral ASIC3 channels are thus essential sensors of acidic pain and integrators of molecular signals produced during inflammation where they contribute to primary hyperalgesia.

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ASIC3, a sensor of acidic and primary inflammatory pain

Acid-sensing ion channels (ASICs): pharmacology and implication in pain.

Acidosis is a noxious condition associated with inflammation, ischaemia or defective acid containment. As a consequence, acid sensing has evolved as an important property of afferent neurons with unmyelinated and thinly myelinated nerve fibres. Protons evoke multiple currents in primary afferent neurons, which are carried by several acid-sensitive ion channels. Among these, acid-sensing ion channels (ASICs) and transient receptor potential (TRP) vanilloid-1 (TRPV1) ion channels have been most thoroughly studied. ASICs survey moderate decreases in extracellular pH, whereas TRPV1 is activated only by severe acidosis resulting in pH values below 6. Two-pore-domain K+ (K2P) channels are differentially regulated by small deviations of extra- or intracellular pH from physiological levels. Other acid-sensitive channels include TRPV4, TRPC4, TRPC5, TRPP2 (PKD2L1), ionotropic purinoceptors (P2X), inward rectifier K+ channels, voltage-activated K+ channels, L-type Ca2+ channels, hyperpolarization-activated cyclic nucleotide gated channels, gap junction channels, and Cl− channels. In addition, acid-sensitive G protein coupled receptors have also been identified. Most of these molecular acid sensors are expressed by primary sensory neurons, although to different degrees and in various combinations. Emerging evidence indicates that many of the acid-sensitive ion channels and receptors play a role in acid sensing, acid–induced pain and acid-evoked feedback regulation of homeostatic reactions. The existence and apparent redundancy of multiple pH surveillance systems attests to the concept that acid–base regulation is a vital issue for cell and tissue homeostasis. Since upregulation and overactivity of acid sensors appear to contribute to various forms of chronic pain, acid-sensitive ion channels and receptors are considered as targets for novel analgesic drugs. This approach will only be successful if the pathological implications of acid sensors can be differentiated pharmacologically from their physiological function.

Acid-Sensitive Ion Channels and Receptors

Peripheral mediators can contribute to the development and maintenance of inflammatory and neuropathic pain and its concomitants (hyperalgesia and allodynia) via two mechanisms. Activation or excit...

Sensory and signaling mechanisms of bradykinin, eicosanoids, platelet-activating factor, and nitric oxide in peripheral nociceptors

Acid-sensing ion channels (ASICs) are a class of ion channels activated by extracellular protons and are believed to mediate the pain caused by tissue acidosis. Although ASICs have been widely studied, little is known about their regulation by inflammatory mediators. Here, we provide evidence that nitric oxide (NO) potentiates the activity of ASICs. Whole-cell patch-clamp recordings were performed on neonatal rat cultured dorsal root ganglion neurons and on ASIC isoforms expressed in CHO cells. The NO donor S-nitroso-N-acetylpenicillamine (SNAP) potentiates proton-gated currents in DRG neurons and proton-gated currents in CHO cells expressing each of the acid-sensitive ASIC subunits. Modulators of the cGMP/PKG pathway had no effect on the potentiation, but in excised patches from CHO cells expressing ASIC2a, the potentiation could be reversed by externally applied reducing agents. NO therefore has a direct external effect on the ASIC ion channel, probably through oxidization of cysteine residues. Complementary psychophysiological studies were performed using iontophoresis of acidic solutions through the skin of human volunteers. Topical application of the NO donor glyceryl trinitrate significantly increased acid-evoked pain but did not affect heat or mechanical pain thresholds. ASICs may therefore play an important role in the pain associated with metabolic stress and inflammation, where both tissue acidosis and a high level of NO are present.

https://www.jneurosci.org/content/jneuro/27/48/13251.full.pdf

Angela Ballard

Papers

Modulation of Acid-Sensing Ion Channel Activity by Nitric Oxide

Ultraviolet‐B induced inflammation of human skin: Characterisation and comparison with traditional models of hyperlagesia