Transient receptor potential channel mediators

Hofmann T., Schaefer M., Schultz G. and Gudermann T. (2000a). Transient receptor potential channels as molecular substrates of receptor-mediated cation entry. J Mol Med 78, 14-25. 

Helliwell RM, Large WA 1997 Alphal-adrenoceptor activation of a non-selective cation current in rabbit portal vein by 1,2-diacyl-sn-glycerol. J Physiol 499 417-428 Hofmann F, Lacinova L, Klugbauer N 1999 Voltage-dependent calcium channels from structure to function. Rev Physiol Biochem Pharmacol 139 33—87 Hofmann T, Schaefer M, Schultz G, Gundermann T 2000 Transient receptor potential channels as molecular substrates of receptor-mediated cation entry. J Mol Med 78 14—25 Inoue R, Okada T, Onoue H et al 2001 The transient receptor potential protein homologue TRP6 is the essential component of vascular aj-adrenoceptor-activated Ca2+-permeable cation channel. Circ Res 88 325—332... 

The carboxyl-terminal 469 amino acids of NompC resemble a class of ion channel proteins called TRP (transient receptor potential) channels. This region includes six putative transmembrane helices with a porelike region between the fifth and sixth helices. The amino-terminal 1150 amino acids consist almost exclusively of 29 ankyrin repeats (Figure 32.35). Ankyrin repeats are structural motifs formed by 33 amino acids folded into a hairpin loop followed by a helix-tum-helix. Importantly, in other proteins, regions with tandem arrays of these motifs mediate protein-protein interactions, suggesting that these arrays couple the motions of other proteins to the activity of the NompC channel. 

Fig. 2 The bitter taste signal transduction cascade. Bitter taste receptors are G-protein-coupled receptors. Activation of TAS2Rs results in the activation of the heterotrimeric G-protein complex a-gustducin (a-gust), 3 or pi, and yl3. The Py-subunits activate phospholipase C P2, (PLCj52) resulting in the production of inositol 1,4,5-trisphosphate (/P3). The IP3-mediated increase of intracellular calcium activates transient receptor potential channel 5 (TRPM5)...

Calcium ions are mostly present in bones or chelated to biological molecules. In blood plasma, only 1% of the calcium ions present are unbound 78% is bound to albumin, 8% to citrate, and 13% to other plasma proteins. The free calcium ions are prevented from precipitating by plasma pyrophosphate. Calcium ions are also stored in the endoplasmic reticulum (ER), mostly chelated to ER-resident proteins and phosphatidylser-ine. Free calcium ions may be released through transient receptor potential channels to the cytosol where it activates numerous physiological processes. If the free calcium ion concentration of blood plasma falls, parathyroid hormone (PTH) is secreted by the parathyroid gland cells. PTH speeds up the transport of demineralized bone products by osteoclasts. In the kidney, it increases the excretion of phosphate and decreases the excretion of calcium. PTH also acts on kidney cells to make calcitriol from vitamin D, which induces calcium transporters in the intestine and osteoclasts. PTH mediates these effects by activating G-protein-coupled receptors in the kidney and osteoclasts. 

Fig. 1 Transient receptor potential vaniUoid 1 (TRPVl) and other transient receptor potential channels expressed in primary sensory neurons and their regulation by inflammatory mediators and exogenous or putative endogenous ligands, NFG nerve growth factor, PAR protease activated receptor 2, B2 bradykinin B2 receptor, ASIC acid-sensing ion channel, EPl/2 prostanoid E receptor...

Vitamin D-mediated transcellular calcium transport also involves entry and extmsion. Calcium influx from the intestine or bone is propelled by a steep electrochemical gradient mediated by the superfamily of Transient Receptor Potential (TRP) ion channels noted above. TRP channel ion selectivity and mode of activation are extremely variable. Some are activated or regulated by ligands such as amino acid amines or small peptides, others by physical stimuli (e.g., heat), and still others by as yet unknown mechanisms. All TRP channels are Ca2+ and Na+ selective, but the selectivity for Ca2+ versus Na+ (Ca/Na ratio) varies enormously from >100 1, to <0.05 1. This variability has contributed to a confusing TRP channel nomenclature. 

Biological target Menthol is a natural terpenoid with agonist activity at the thermoreceptive, non-selective cation channel, transient receptor potential mela-statin type 8 (TRPM8). Present on nerve fibres and skin cells, these channels are activated by a fall in temperature and mediate analgesia. Menthol is also an agonist at GABAa receptors, for which (+)-menthol reveals stereoselectivity. 

Mediator-induced inflammatory processes can lead to increased vascular permeability, neurogenic inflammation of airways and blood vessels, chemotaxis, and bronchospasm (Smith and Topford, 1999). Furthermore, capsaicin activates the vanilloid receptor family TRPVl (transient receptor potential cation channel subfamily V) within sensory neurons. Activation of these receptors leads to prolonged refractory periods and to a nonconducting desensitization. One study suggests that TRPV pathways may not be enhrely responsible for all of the adverse reactions caused by capsaicin (Holzer, 1991). 

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