The Pivotal Role of TRP Channels in Homeostasis and Diseases throughout the Gastrointestinal Tract

Abstract

The transient receptor potential (TRP) channels superfamily are a large group of proteins that play crucial roles in cellular processes. For example, these cation channels act as sensors in the detection and transduction of stimuli of temperature, small molecules, voltage, pH, and mechanical constrains. Over the past decades, different members of the TRP channels have been identified in the human gastrointestinal (GI) tract playing multiple modulatory roles. Noteworthy, TRPs support critical functions related to the taste perception, mechanosensation, and pain. They also participate in the modulation of motility and secretions of the human gut. Last but not least, altered expression or activity and mutations in the TRP genes are often related to a wide range of disorders of the gut epithelium, including inflammatory bowel disease, fibrosis, visceral hyperalgesia, irritable bowel syndrome, and colorectal cancer. TRP channels could therefore be promising drug targets for the treatment of GI malignancies. This review aims at providing a comprehensive picture of the most recent advances highlighting the expression and function of TRP channels in the GI tract, and secondly, the description of the potential roles of TRPs in relevant disorders is discussed reporting our standpoint on GI tract–TRP channels interactions.

Atomistic Insights of Calmodulin Gating of Complete Ion Channels

“…There is a sharp turn following helix B, so helix C goes perpendicular to the membrane forming a loose bundle between the four subunits, in line with the tendency of helix C to form weak dimers in vitro [101]. A flexible sequence with no conservation among KCNQ subunits follows to link with helix D that forms a coiled-coil tetramer, a feature also observed in Eag1 and SK channels [21]. The global architecture is notably similar to that of SK channels, with the CaM C-lobe also engaging helix A almost with the same orientation, even at the lateral chain level [35].…”

“…The functional compensation of ∆7-12 by a S4/5 mutation, the proximity of the PAS-Cap in the open conformation of hERG [33], and the impact of ∆3-9 and R7A/R8A mutant on function, suggest that R7/R8 might form a functional interaction with D342 in S4/5 [20]. Mutation-function studies suggest that PAS-Cap can be divided into two segments, the unstructured N-terminus (residues 1-9, not seen in the cryo-EM structures) and the unstructured C-terminal (residues 10-13) that precedes the amphipathic alpha helix (residues [16][17][18][19][20][21][22][23][24][25]. The N-terminus seems to promote opening, whereas the C-terminus appears to promote closure [20].…”

Nature-Identical Compounds and Organic Acids Ameliorate and Prevent the Damages Induced by an Inflammatory Challenge in Caco-2 Cell Culture

“…Furthermore, the modulation of these channels from OA + NIC, with an increased expression of TRPV1 and a reduction of TRPV3, support the hypothesis of the anti-inflammatory potential of the mixture. In fact, TRPV1 and TRPV3 are known for their anti-inflammatory [ 36 ], and pro-inflammatory [ 5 ] action, respectively. Moreover, the cytokine cascade induced by the host inflammatory response has a direct effect on TJ proteins.…”

“…Moreover, recent outcomes have highlighted the role of transient potential receptor vanilloid (TRPV) channels in modulating inflammation, while their precise role is still under investigation. In fact, TRPV channels are reported both as pro-inflammatory and as anti-inflammatory [ 5 , 6 ]. When intestinal barrier failure occurs, the concentration of pro-inflammatory cytokines, produced by the lamina propria, increases [ 7 ], which negatively influences intestinal integrity, and leading to a reduction in intestinal functionality [ 8 , 9 ].…”

Role of TRP Channels in Shaping the Gut Microbiome

“…At a cellular level, TRP channel proteins perform several functional roles in the gastrointestinal tract. These primarily include their role as molecular sensors and transductors of chemical and physical stimuli, and as effectors of ion channels and receptors, modulating the transport of cations across the plasma membrane [ 52 ]. TRP proteins are involved in various cellular functions due to their varied permeability to cations and their ability to influence intracellular Ca 2+ and Mg 2+ signaling [ 53 ].…”