TRP channels in neurogastroenterology: opportunities for therapeutic intervention

Abstract

The members of the superfamily of transient receptor potential (TRP) cation channels are involved in a plethora of cellular functions. During the last decade, a vast amount of evidence is accumulating that attributes an important role to these cation channels in different regulatory aspects of the alimentary tract. In this review we discuss the expression patterns and roles of TRP channels in the regulation of gastrointestinal motility, enteric nervous system signalling and visceral sensation, and provide our perspectives on pharmacological targeting of TRPs as a strategy to treat various gastrointestinal disorders. We found that the current knowledge about the role of some members of the TRP superfamily in neurogastroenterology is rather limited, whereas the function of other TRP channels, especially of those implicated in smooth muscle cell contractility (TRPC4, TRPC6), visceral sensitivity and hypersensitivity (TRPV1, TRPV4, TRPA1), tends to be well established. Compared with expression data, mechanistic information about TRP channels in intestinal pacemaking (TRPC4, TRPC6, TRPM7), enteric nervous system signalling (TRPCs) and enteroendocrine cells (TRPM5) is lacking. It is clear that several different TRP channels play important roles in the cellular apparatus that controls gastrointestinal function. They are involved in the regulation of gastrointestinal motility and absorption, visceral sensation and visceral hypersensitivity. TRP channels can be considered as interesting targets to tackle digestive diseases, motility disorders and visceral pain. At present, TRPV1 antagonists are under development for the treatment of heartburn and visceral hypersensitivity, but interference with other TRP channels is also tempting. However, their role in gastrointestinal pathophysiology first needs to be further elucidated.

Figure 1

Schematic of the general activation mechanisms of the transient receptor potential (TRP) channels discussed in this review. TRPs are intrinsic membrane proteins that allow the passage of cations. Except for TRPM4 and TRPM5, all TRP channels are Ca²⁺-permeable cation channels but their selectivity for mono- and divalent cations varies greatly among different TRPs. The activation mechanism of TRP channels is unclear in many cases, but known activators include specific agonists such as capsaicin (TRPV1) and mustard oil (TRPA1), an increase in intracellular Ca²⁺ (TRPM4, 5), temperature (heat: TRPV1, 2, 3, 4, TRPM4, 5; cold: TRPM8, TRPA1), mechanical or osmotic stress (TRPV4, TRPCs?) and phospholipase C (PLC) activation. Cell swelling activates TRPV4 via the PLA₂-pathway. G-protein-coupled receptor (GPCR) activation activates several TRP channels via PLC and diacylglycerol (DAG) dependent mechanisms. Intracellular Ca²⁺ also activates many TRP channels including TRPM5. TRPC3 and TRPC6 are activated by store depletion via a so far unknown mechanism. Several TRP channels are furthermore modulated by depolarization, temperature, intracellular phosphatidylinositol phosphates, such as PI(4,5)P₂, but also by inflammatory mediators and steroids. TRP channels control cell functions by directly permitting Ca²⁺ influx into the cell in response to specific stimuli, or through depolarization of the membrane potential due to cation influx. They can also influence Ca²⁺ entry through other ion channels, such as voltage-gated Ca²⁺ channels (VGCC). EET: 5,6-epoxyeicosatrienoic acids; SERCA: sarco/endoplasmic reticulum Ca²⁺-ATPase. For more details, see text.

Figure 2

Schematic overview of transient receptor potential (TRP) channel distribution in the gastrointestinal (GI) tract. TRP channels can be found at almost all levels of GI control but their role remains rather elusive in most cases. In the GI mucosa, TRPs are expressed by enterocytes and different types of enteroendocrine (EEC, green) cells including enterochromaffin (EC, red) cells. They are involved in several epithelial functions such as nutrient sensing (TRPM5) and chlorhydropeptic secretion (TRPV1). Some TRP channels, especially TRPCs, are expressed by subtypes of enteric neurons in both the myenteric (MP, blue) and submucosal plexus (SMP, pink), yet knowledge about their function in the enteric nervous system is limited. Smooth muscle cells in the circular (CM) and longitudinal muscle (LM) layers also express TRPCs. More specifically, TRPC4 and TRPC6 play a role in muscarinic receptor-induced smooth muscle cell depolarization. Together with TRPM7, TRPC4 and TRPC6 are also implicated in the generation of pacemaker currents by interstitial cells of Cajal (ICC, yellow) but their exact function in the generation of slow waves is still debated. Apart from being involved in the intrinsic control of GI functions, a vast amount of data also points to a crucial role for TRP channels in visceral sensation by extrinsic afferents. Especially TRPs that are involved in different aspects of sensory perception such as temperature, pressure and pain are expressed by both spinal (purple) and vagal (maroon) afferents. TRPV1, 2, 4, TRPA1 and TRPM8 channels are shown to mediate visceral mechano-, chemo-, thermo- and nociception and are also implicated in visceral hypersensitivity in diseased states such as irritable bowel syndrome. The role of TRPM4 also deserves attention because factors released by these cells influence hypersensitivity to a large extent. For more details, see text.