Chapter

Sensory Nerves

Volume 194 of the series Handbook of Experimental Pharmacology pp 283-332

Date:

Acid-Sensitive Ion Channels and Receptors

  • Peter HolzerAffiliated withResearch Unit of Translational Neurogastroenterology, Institute of Experimental and Clinical Pharmacology, Medical University of Graz Email author 

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Abstract

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.

Keywords

Acid surveillance Acid-induced pain Sour taste Acidosis Ischaemia Angina pectoris Inflammation Acid-related gastrointestinal diseases Cough Bone resorption Gastrointestinal tract Urogenital tract Pulmonary system Skin Carotid body Proton-gated currents Molecular acid sensors Acid-sensing ion channels ASIC3 TRP ion channels TRPV1 TRPP2 Two pore domain potassium channels TASK channels Proton-sensing G protein coupled receptors Ionotropic purinoceptors