TRPV-1 receptor

In the brain stem, TRPV1 receptor activation, similarly to P2X3 receptor activation (see above), facilitated spontaneous glutamate release in a tetrodotoxin- and Cd2+-insensitive manner, even though the two presynaptic receptors were located on different primary afferent fibres (Jin et al. 2004). Action potential-dependent glutamate release, in contrast, was reduced by TRPV 1 activation (Doyle et al. 2002). In paraventricular neurons, TRPV 1 receptor activation facilitated spontaneous glutamate release in a tetrodotoxin- and Cd2+-insensitive way, but in that case evoked glutamate release was enhanced too (Li et al. 2004). 

Cabranes A, Venderova K, de Lago E, Fezza F, Valenti M, Sdnchez A, Garcfa-Merino A, Ramos JA, Di Marzo V, Fernandez-Ruiz J (2005) Decreased endocannabinoid levels in the brain and beneficial effects of certain endocannabinoid uptake inhibitors in a rat model of multiple sclerosis involvement of vanilloid TRPV 1 receptors. Neurobiol Dis (in press)... 

In the bronchus, LOX inhibitors modestly attenuate the contractile action of capsaicin (Craib et al., 2001), raising the possibihty that the increase in intracellular calcium elicited by TRPV 1 receptor activation leads to the release of arachidonic add or anandamide or both, whose hydrox-ylation by LOX may lead to the formation of compounds that are themselves vanilloid agonists. 

Potent FAAH inhibitors have recently been synthesized that enhance the levels of anandamide significantly, and these compounds may have considerable therapeutic potential (Boger et al., 2000). In the event of inhibition of FAAH metabolism of anandamide, increased levels of endogenous anandamide may lead to the production of significant levels of the HPETE ethanolamides. In addition, LOX metabolism producing metabolites that are FAAH inhibitors (van der Stelt et al., 2002) of anandamide may enhance TRPV 1 receptor activation by increasing the levels of available anandamide. 

A number of the inflammatory mediators mentioned above have the ability to activate the TRPV-1 receptor indirectly by activation of the protease-activated receptors and through protein kinase dependent pathways(Dai et al. 2004 Gath et al. 2006 Ramachandran et al. 2007). 

Vitamin D is a fat soluble vitamin related to cholesterol. In the skin, sunlight spontaneously oxidizes cholesterol to 7-dehydrocholesterol. 7-Dehydrocholesterol spontaneously isomerizes to cholecalciferol (vitamin D3), which is oxidized in the liver to 25-hydroxy cholecalciferol and, under the influence of PTH in the kidney, to 1,25-dihy-droxy cholecalciferol (calcitriol), the active form of vitamin D. Vitamin D induces the expression of calcium ion transport proteins (calbindins) in intestinal epithelium, osteoclasts, and osteoblasts. Calbindins and transient receptor potential channels (TRPV) are responsible for the uptake of calcium from the diet. In children, the absence of sunlight provokes a deficiency of vitamin D, causing an absence of calbindins and inadequate blood calcium levels. Osteoid tissue cannot calcify, causing skeletal deformities (rickets). In the elderly, there is a loss of intestinal TRPV receptors and decreased calbindin expression by vitamin D. In both cases, the resultant low blood calcium levels cause poor mineralization during bone remodeling (osteomalacia). Rickets is the childhood expression of osteomalacia. Osteoclast activity is normal but the bone does not properly mineralize. In osteoporosis, the bone is properly mineralized but osteoclasts are overly active. 

Ji RR, Samad TA, Jin SX, et al. (2002) p38 MAPK activation by NGF in primary sensory neurons after inflammation increases TRPVl levels and maintains heat hyperalgesia. Neuron 36 57-68 Jia Y, Lee LY (2007) Role of TRPV receptors in respiratory diseases. Biochim Biophys Acta 1772 915-927... 

Capsaican is a TRPV-1 agonist. TRPVl (also termed the capsaican receptor) is a polymodal nociceptor exhibiting a dynamic threshold of activation that is markedly reduced in inflammatory conditions [3]. TRPVl knock-out mice are devoid of post-inflammatory thermal hyperalgesia. TRPV receptors are in abundance on unmyelinated C fiber peripheral endings and respond to a variety of noxious mediators. Once activated these fibers transmit localized and... 

The TRPV receptor contains six transmembrane domains designated S1-S6. These domains anchor the channel to the cellular membrane. Between S5 and S6 there is a pore. TRPV possess three ankyrin repeats. This transmembrane protein has an extracellular surface and an intracellular surface (Figure 128.3). Factors that activate and regulate this channel act in different domains. Antagonists of this channel may act in different areas of the complex molecule, the pore, the capsaicin site, the extracellular area, or the intracellular area, leading to its inactivation. 

Fig. 1 Structures of subunits (top) and subunit oligomerization (bottom) in ligand-gated ion channels. (a) P2X receptor family, (b) Ionotropic glutamate receptor family, (c) TRPV channel family, (d) Cys-loop superfamily comprising nAChRs, 5-HT3,GABAa, and glycine receptors.

Highly sensitive targeted lipidomic approaches are rapidly leading to the identification of new analogs of anandamide (Tan et al., 2006). The two major families of lipids that share common chemical structure with anandamide are FAEs and fatty acid amides. Although many of these lipids show no activity at CB receptors, they are known to bind and activate other receptors, such as transient receptor potential vanilloid type-1 (TRPV-1) and the nuclear receptor peroxisome proliferator-activated (PPAR-a). 

TRP —transient receptor potential channel TRPA—TRP ankyrin receptor subfamily TRPC—TRP canonical receptor subfamily TRPM—TRP melastatin receptor subfamily TRPML—TRP mucolipin receptor subfamily TRPN—TRP NOMPG receptor family TRPP—TRP polycystin receptor subfamily TRPV—TRP vanilloid receptor subfamily TTX—tetrodotoxin... 

TRP channels, named for their role in Drosophila phototransduction, are a family of hexas-panning receptors with a pore domain between the fifth and sixth transmembrane segments and a common 25-amino acid TRP box C-terminal of the sixth transmembrane domain these channels are found across the phylogenetic scale from bacteria to mammals. Members of the TRPV subfamily serve as the receptors for endogenous cannabinoids, such as anandamide, and the hot pepper toxin, capsaicin. 

Mezey E, Toth ZE, Cortright DN, Arzubi MK, Krause JE, Elde R, Guo A, Blumberg PM, Szallasi A. Distribution of mRNA for vanilloid receptor subtype 1 (TRPVl), and TRPV 1-like immunoreactivity, in the central nervous system of the rat and human. Proc. Natl. Acad. Sci. U.S.A. 97,3655-3660 (2000). 

RARs rapidly adapting receptors, TRPV-l transient receptor potential vaniUoid-1, AA arachidonic acid, 5-HT 5-hydroxytryptamine, ASIC acid-sensing ion channel, BKB2 bradykinin B2... 

Fig. 2 Afferent pathways and central control of the cough reflex with peripheral and central sensitization of the reflex by a variety of mechanisms. CGRP calcitonin gene-related peptide, tiTS nucleus of the solitary tract, LTD4 leukotriene D4, NK neurokinin, PGE2 prostaglandin E2, RAR rapidly adapting receptors, SAR slowly adapting receptors, TRPV-1 transient receptor potential vanUloid-l...

---