TRP Channels and Pain

Excerpt

Pain is one of the primary responses developed by our body to protect us from harm. However, there are numerous pathological conditions, such as diabetes, viral infections, nerve damage, and inflammation that produce persistent pain. Chronic pain has no apparent useful purpose and is, in most cases, refractory to current pharmacological treatments.

Following the onset of a painful peripheral stimulus, nociceptive neurons are activated to initiate a cascade of action potentials that propagate along the axons of the primary afferent fibers (C and Aδ fibers) to the nerve terminals found in laminae I and II of the dorsal horn in the spinal cord (Figure 8.1a). These nerve terminals release neurotransmitters such as glutamate, substance P, and calcitonin gene-related peptide (CGRP) to activate postsynaptic receptors located in spinothalamic tract neurons (Boadas-Vaello et al., 2016). The projections that reach the thalamus function in pain perception (Figure 8.1b). A variety of receptors and ion channels propagate and process pain signals.

Nociceptive neurons send signals from the periphery, through the afferent fibers, to the visceral, trigeminal, and somatic regions, and also connect the spinal cord to the brain, thus serving as mediators in painful stimulus transmission between the central and peripheral nervous systems (CNS and PNS) (Figure 8.1a). These neurons express a wide variety of receptors and ion channels that are distributed along the fibers and the somas. These are the molecules that detect noxious stimuli, transforming them into electrical signals and directing them to the CNS (Dubin and Patapoutian, 2010). The most important ion channel family that detects and transmits noxious stimuli is the transient receptor potential (TRP) channel family. This family contains proteins that are conserved nonselective calcium-permeable channels (Julius, 2013). In general, TRP channels act as molecular sensors of multiple stimuli, ranging from changes in pH, chemical agents, temperature, and osmolarity. The TRP family of ion channels is composed of 28 members divided into six subfamilies, classified as canonical (TRPC), vanilloid (TRPV), ankyrin (TRPA), melastatin (TRPM), polycystin (TRPP), and mucolipin (TRPML) (Wu et al., 2010).

The TRP channel structure varies considerably; however, there are certain shared domains that allow them to be grouped into the six subfamilies mentioned above. TRP channels consist of four subunits, each containing six transmembrane segments (S1–S6). A hydrophilic loop between the S5 and S6 forms the ion-conducting pore. The amino acids located before the pore confer channel selectivity. These channels are nonselective for cations but have preference for calcium (Owsianik et al., 2006b).

The most highly variable regions within the TRP channel sequences are the carboxyl and amino terminal ends. The ankyrin repeat is located at the amino terminus of the TRPC, TRPA, and TRPV subfamilies. The TRP box, which is a conserved six amino acid sequence found in the TRPC, TRPM, TRPA, and TRPV subfamilies, is located at the carboxyl end, and several studies have shown that the TRP box is important for channel gating (Valente et al., 2008). In addition to the ankyrin repeat and TRP box domains, TRP family members contain other domains, including the EF-hand, PDZ, or NUDIX domains. These domains are distributed among various TRP family members (Owsianik et al., 2006a). Because of their diversity in domain structures, TRP channels are able to respond to a wide variety of stimuli and form complexes with multiple proteins involved in different cellular processes. The ability to respond to different stimuli has positioned the TRP channels as the primary channels responsible for nociception in physiological and pathophysiological conditions such as chronic pain. In this chapter, we summarize the most relevant findings related to the TRPA, TRPM, and TRPV subfamilies in nociception and their importance in pain development and maintenance.