Evolution of acid nociception: ion channels and receptors for detecting acid

Abstract

Nociceptors, i.e. sensory neurons tuned to detect noxious stimuli, are found in numerous phyla of the Animalia kingdom and are often polymodal, responding to a variety of stimuli, e.g. heat, cold, pressure and chemicals, such as acid. Owing to the ability of protons to have a profound effect on ionic homeostasis and damage macromolecular structures, it is no wonder that the ability to detect acid is conserved across many species. To detect changes in pH, nociceptors are equipped with an assortment of different acid sensors, some of which can detect mild changes in pH, such as the acid-sensing ion channels, proton-sensing G protein-coupled receptors and several two-pore potassium channels, whereas others, such as the transient receptor potential vanilloid 1 ion channel, require larger shifts in pH. This review will discuss the evolution of acid sensation and the different mechanisms by which nociceptors can detect acid. This article is part of the Theo Murphy meeting issue 'Evolution of mechanisms and behaviour important for pain'.

Keywords: TRP channel; acid; acid-sensing ion channel; nociception; proton-sensing GPCR; two-pore potassium channel.

Figure 1.

Membrane topologies of proton-sensitive receptor subunits. Schematic diagram of the basic structure of proton-sensitive receptors, with residues or regions important for proton sensitivity annotated (yellow—highly conserved among family members; white—less conserved or important in some, but not all, family members). Functional ASICs, K2Ps and TRPs are multimeric, but for simplicity only one subunit of each receptor is shown.

Figure 2.

Phylogeny of general nociception and acid nociception. Annotated phylogenetic tree indicating the presence of general nociceptors, observation of acid nociception and functional expression of proton-sensitive receptors. Annotation is limited by the rarity of molecular studies focusing on lower-order species. Expression of proton-sensitive receptors is only acknowledged for those species where proton sensitivity of at least one member of the group in question has been empirically proven. For simplicity only species addressed in this review are shown.

Figure 3.

Proton-sensation at the peripheral terminal of a typical nociceptor. Following localized acidosis, the increased extracellular concentration of protons is sensed by several receptors which act in concert to increase neuronal excitability and release mediators which may sensitize other neurons. Increased extracellular proton concentration induces the activation of proton-sensitive depolarizing channels (ASICs and TRPs) causing cation influx and membrane depolarization. Simultaneously, proton-induced inhibition of K2P channels reduces constitutive K⁺ efflux further facilitating membrane depolarization. Activation of PS-GPCRs can drive changes in gene expression and coordinate phosphorylation and sensitization of TRP channels. Altogether, nociceptor membrane depolarization activates Na_V subunits resulting in generation of action potentials that transmit nociceptive signals to the spinal cord. (*Amino acid variations in Na_V1.7 of some species renders the channel hypersensitive to proton-block resulting in an absence of proton-induced nociception.)