Acid-sensitive ion channels and receptors

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(+) (K(2P)) 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 Ca(2+) 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.

Figure 1

Overview of ion channel subunits and receptors that are modulated by changes in the extracellular pH (acidification) and expressed by primary afferent neurons or their associated cells. For details see text.

Figure 2

Membrane topology of 4 classes of acid-sensitive ion channel subunits: ASIC (acid-sensing ion channel), TRPV (transient receptor potential ion channel of the vanilloid subtype), P2X (ionotropic purinoceptor) and KCNK (K_2P ion channel). A, ankyrin; C, COOH terminal; N, NH₂ terminal; P, pore; TM, transmembrane domain.

Figure 3

Overview of the TRP channel subfamilies and of the acid-sensitive subunit members among the TRPC, TRPP and TRPV subfamilies. For details see text.

Figure 4

Overview of the K_2P channel subunit families and of the subunit members (indicated in bold and italics) that are modulated by changes in the extracellular pH. For details see text.

Figure 5

Overview of the pathophysiological implications of acid-sensitive ion channels in afferent neuron function, based primarily on pharmacological antagonist and gene disruption studies. For details see text.