Disease relevance of TRPV1

• FINDINGS: In rectal hypersensitivity, nerve fibres immunoreactive to TRPV1 were increased in muscle, submucosal, and mucosal layers: in the mucosal layer, the median% area positive was 0.44 (range 0.30-0.59) in patients who were hypersensitive and 0.11 (0.00-0.21) in controls (p=0.0005) [1].
• This process, called sensitization or hyperalgesia, is mediated by a variety of proinflammatory factors, including bradykinin, ATP and NGF, which cause sensitization to noxious heat stimuli by enhancing the membrane current carried by the heat- and capsaicin-gated ion channel, TRPV1 [2].
• In primary dorsal root ganglion neurons, TRPV1 co-distributes in vesicles with Syt IX and the vesicular protein synaptobrevin [3].
• Based on our data we propose a model of the TM3/4 region of TRPV1 bound to capsaicin or RTX that may aid in the development of potent TRPV1 antagonists with utility in the treatment of sensory disorders [4].
• These findings strongly support TRPV1 as a significant novel player in human hair growth control, underscore the physiological importance of TRPV1 in human skin beyond nociception, and identify TRPV1 as a promising, novel target for pharmacological manipulations of epithelial growth disorders [5].

Psychiatry related information on TRPV1

• As systemic administration of TRPV1 ligands reduces locomotor activity in normal rodents, we hypothesised that activation of TRPV1 by endocannabinoids could play a role in the control of voluntary movement and that such actions could be regulated by AMT and FAAH [6].
• The translated gene shares 46% and 43% identity with VR1 and VRL-1, respectively, and maps to chromosome 12q23-24.1, a locus associated with bipolar affective disorder [7].
• Invertebrate TRPV channels, five in Caenorhabditis elegans and two in Drosophila, have been shown to play a role in mechanosensation, such as hearing and proprioception in Drosophila and nose touch in C. elegans, and in the response to osmotic stimuli in C. elegans [8].
• For both rVR1 and hVR1, time-response waveforms elicited by resiniferatoxin increased more gradually compared to other agonists [9].

High impact information on TRPV1

• On the basis of these properties, we propose that hTRPV3 is thermosensitive in the physiological range of temperatures between TRPM8 and TRPV1 [10].
• Furthermore, when heterologously expressed, VRL3 is able to associate with VR1 and may modulate its responses [11].
• Vanilloid receptor-1 (VR1, also known as TRPV1) is a thermosensitive, nonselective cation channel that is expressed by capsaicin-sensitive sensory afferents and is activated by noxious heat, acidic pH and the alkaloid irritant capsaicin [11].
• VRL3 responds to noxious heat with a threshold of about 39 degrees C and is co-expressed in dorsal root ganglion neurons with VR1 [11].
• VRL3 is coded for by a 2,370-base-pair open reading frame, transcribed from a gene adjacent to VR1, and is structurally homologous to VR1 [11].

Chemical compound and disease context of TRPV1

• These results suggest that the decreased expression of TRPV1 may be related to a functional knock out in capsaicin sensation and hypersensitivity to allicin in humans [12].
• Vasorelaxation by abn-cbd is endothelium-dependent, pertussis toxin-sensitive, and is inhibited by the BK(Ca) channel inhibitor charybdotoxin, but not by the nitric-oxide synthase inhibitor N(omega)-nitro-L-arginine methyl ester or by the vanilloid VR1 receptor antagonist capsazepine [13].
• Arachidonylethanolamide induces apoptosis of human glioma cells through vanilloid receptor-1 [14].
• Further examinations revealed that TRPV1-induced toxicity was accompanied by increases in intracellular Ca(2+), and mitochondrial damage; these effects were inhibited by capsazepine, I-RTX, and the intracellular Ca(2+) chelator BAPTA-AM [15].
• In the present study, we determined whether 5-HT changes TRPV1 functions in cultured dorsal root ganglion (DRG) neurons isolated from neonatal rats, using Ca(2+) imaging and whole-cell patch-clamp techniques [16].

Biological context of TRPV1

• Phosphorylation of TRPV1 at a single tyrosine residue, Y200, followed by insertion of TRPV1 channels into the surface membrane, explains most of the rapid sensitizing actions of NGF [2].
• In organ culture, TRPV1 activation by capsaicin resulted in a dose-dependent and TRPV1-specific inhibition of hair shaft elongation, suppression of proliferation, induction of apoptosis, premature HF regression (catagen), and up-regulation of intrafollicular transforming growth factor-beta(2) [5].
• Therefore, our results indicate that PKC signaling promotes at least in part the SNARE-dependent exocytosis of TRPV1 to the cell surface [3].
• High expression of TRPV1 has been detected in several inflammatory diseases of the colon and ileum, whereas neuropeptides released upon sensory nerve stimulation triggered by TRPV1 activation seem to play a role in intestinal motility disorders [17].
• Thus, capsaicin interacted with TRPV1 expressed by BEAS-2B and other airway epithelial cells to cause the calcium-dependent production of cytokines and, conversely, calcium-independent cell death [18].

Anatomical context of TRPV1

• Here, we show that intracellular Ca2+ mobilization via the purinergic receptor agonist ATP, the muscarinic receptor agonist carbachol or the Ca(2+)-ATPase inhibitor thapsigargin leads to formation of anandamide, and subsequent TRPV1-dependent Ca2+ influx in transfected cells and sensory neurons of rat dorsal root ganglia (DRG) [19].
• Extracellular Ca2+-dependent desensitization of TRPV1 observed in patch-clamp experiments when using both heterologous expression systems and native sensory ganglia is thought to be one mechanism underlying the paradoxical effectiveness of capsaicin as an analgesic therapy [20].
• TRPV1 was originally described on sensory neurons as a central integrator of various nociceptive stimuli [5].
• In addition, low levels of 2APB strongly potentiate the effect of capsaicin, protons, and heat on TRPV1 as well as that of heat on TRPV3 expressed in Xenopus oocytes [21].
• Noteworthily, we found that PKC activation induced a rapid delivery of functional TRPV1 channels to the plasma membrane [3].

Associations of TRPV1 with chemical compounds

• The natural compounds capsaicin and menthol activate noxious heat-sensitive TRPV1 and cold-sensitive TRPM8, respectively [22].
• As yet, endogenously produced anandamide has not been shown to activate TRPV1, but this is of importance to understand the physiological function of this interaction [19].
• Furthermore, these residues account for the reported pharmacological differences of RTX, PPAHV (phorbol 12-phenyl-acetate 13-acetate 20-homovanillate) and capsazepine between human and rat TRPV1 [4].
• We found that forskolin, a stimulator of adenylate cyclase, decreased desensitization of TRPV1 [23].
• We propose that residue Y671 is critical for the high relative Ca(2+) permeability of TRPV1 and participates in the structural rearrangements of the channel protein leading to Ca(2+)-dependent desensitization [24].

Physical interactions of TRPV1

• ECaC constitutes the rate-limiting apical entry step in the process of active transcellular Ca(2+) transport and belongs to a superfamily of Ca(2+) channels that includes the vanilloid receptor and transient receptor potential channels [25].
• Interestingly, TRPV1 binding was increased in the striatum of DAT KO mice, while CB1 receptor binding was unaffected [26].
• Several receptors including G-protein coupled prostaglandin receptors have been reported to functionally interact with the TRPV1 through a cAMP-dependent protein kinase A (PKA) pathway to potentiate TRPV1-mediated capsaicin responses [27].

Regulatory relationships of TRPV1

• We found that CGRP-expressing fibers in the pancreatic islets also express TRPV1 [28].
• Double labeling analysis revealed that TRPM8 immunoreactivity was co-expressed with a part of TRPV1 or CGRP-immunoreactive neurons in TG [29].
• The vanilloid receptor family of cation channels includes the capsaicin-sensitive, proton- and heat-activated TRPV1 and noxious heat-activated TRPV2 [30].
• TRPV4 is a widely expressed cation channel of the 'transient receptor potential' (TRP) family that is related to the vanilloid receptor VR1 (TRPV1) [31].
• We also confirm the importance of TRPA1 in WIN-induced dephosphorylation of TRPV1 in Chinese hamster ovary cells through targeted expression of one or both receptor channels [32].

Other interactions of TRPV1

• Our data suggest the existence of a common activation mechanism for TRPV1, TRPV2, and TRPV3 that may serve as a therapeutic target for pain management and treatment for diseases caused by hypersensitivity and temperature misregulation [21].
• With the exception of TRPV5 and TRPV6, TRPV channel subunits preferentially assemble into homomeric complexes [33].
• The lipoxygenase and epoxygenase products of arachidonic acid (AA) metabolism have been shown to directly activate TRPV1 and TRPV4, respectively [34].
• These effects were accompanied by enhanced insulin secretion and a virtually complete loss of CGRP- and TRPV1-coexpressing islet-innervating fibers [28].
• In normal rats, the TRPV1 agonist capsaicin (1mg/kg) or the FAAH inhibitor URB597 (10mg/kg) caused a significant reduction in movement in both the horizontal (locomotion) and vertical (rearing) planes (-45% and -53% respectively with capsaicin; -33% and -37% for URB597) [6].

Analytical, diagnostic and therapeutic context of TRPV1

• Sequence alignment of segments 6 of TRPV1 and voltage-gated Na(+) channels reveals a conserved aromatic amino acid that in Na(+) channels is involved in fast inactivation and pharmacological block [24].
• Two heat sensitive channels, TRPV1 and TRPV4, and a cold-sensitive channel, TRPA1, were detected by RT-PCR [35].
• Here, we examined expression patterns of the voltage-gated potassium channel Kv1.4, the nociceptive transduction channels TRPV1 and TRPV2 as well as the putative anti-nociceptive cannabinoid receptor CB1 by immunofluorescence double-labelings in sections of rat dorsal root ganglia (DRGs) [36].
• Secondly, using in situ hybridization, TRPV1 mRNA- or TRPA1 mRNA-labeled neurons (signal/noise ratio >or= 10) were observed in 15-20% of GG neurons [37].
• Retrogradely labelled dorsal root ganglion neurons were subjected to triple-labelling immunohistochemistry using antisera against TRPV1, ASIC3 and neurofilament 68 (marker for myelinated neurons), and their soma diameter was measured [38].

References