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PubMed2006

TRPA1 is a substrate for de-ubiquitination by the tumor suppressor CYLD.

Certain TRP cation channels confer the ability to sense environmental stimuli (heat, cold, pressure, osmolarity) across physiological and pathophysiological ranges. TRPA1 is a TRP-related channel that responds to cold temperatures, and pungent compounds that include the cold-mimetic icilin and cannabinoids. The initial report of TRPA1 as a transformation-associated gene product in lung epithelia is at odds with subsequent descriptions of a tissue distribution for TRPA1 that is restricted to sensory neurons. Here, we report that the human TRPA1 protein is widely expressed outside the CNS, and is indeed dys-regulated during oncogenic transformation. We describe that TRPA1 associates with the tumor-suppressor protein CYLD. TRPA1 is a novel substrate for the de-ubiquitinating activity of CYLD, and this de-ubiquitination has the net effect of increasing the cellular pool of TRPA1 proteins. Oncogenic mutations in the CYLD gene may therefore be predicted to alter cellular levels of TRPA1.

Calcium Channels↗
PubMed2006

TRPML cation channels regulate the specialized lysosomal compartment of vertebrate B-lymphocytes.

B-lymphocytes possess a specialized lysosomal compartment, the regulated transformation of which has been implicated in B-cell antigen presentation. Members of the mucolipin (TRPML) family of cation channels have been implicated in regulated vesicular transport in several tissues, but a role for TRPML function in lymphocyte vesicular transport physiology has not been previously described. To address the role of TRPML proteins in lymphocyte vesicular transport, we analyzed the lysosomal compartment in cultured B-lymphocytes engineered to lack TRPML1 or after expression of N- or C-terminal GFP fusion proteins of TRPML1 or TRPML2. Consistent with previous analyses of lymphocytes derived from human patients with mutations in TRPML1, we were not able to detect abnormalities in the lysosomes of TRPML1-deficient DT40 B-lymphocytes. However, while N-terminal GFP fusions of TRPML2 localized to normal appearing lysosomes, C-terminal GFP fusions of either TRPML1 or TRPML2 acted to antagonize endogenous TRPML function, localizing to large vesicular structures, the histological properties of which were indistinguishable from the enlarged lysosomes observed in affected tissues of TRPML1-deficient humans. Endocytosed B-cell receptors were delivered to these enlarged lysosomes, demonstrating that a TRPML-dependent process is required for normal regulation of the specialized lysosome compartment of vertebrate B-lymphocytes.

Animals↗
PubMed2005

Expression of the transient receptor potential vanilloid 1 (TRPV1) in LNCaP and PC-3 prostate cancer cells and in human prostate tissue.

Vanilloid receptor subtype-1 (TRPV1), the founding member of the vanilloid receptor-like transient receptor potential channel family, is a non-selective cation channel that responds to noxious stimuli such as low pH, painful heat and irritants. In the present study, we show, as means of reverse transcriptase-polymerase chain reaction and Western blot analysis, that the vanilloid TRPV1 receptor is expressed in the prostate epithelial cell lines PC-3 and LNCaP as well as in human prostate tissue. The kinetic parameters inferred from [(125)I]-resiniferatoxin binding were in concordance with data of TRPV1 receptors expressed in other tissues. The contribution of the endogenously expressed TRPV1 channel to intracellular calcium concentration increase in the prostate cells was studied by measuring changes in Fura-2 fluorescence by fluorescence microscopy. Addition of capsaicin, (R)-methanandamide and resiniferatoxin to prostate cells induced a dose-dependent increase in the intracellular calcium concentration that was reversed by the vanilloid TRPV1 receptor antagonist capsazepine. These results indicate that the vanilloid TRPV1 receptor is expressed and functionally active in human prostate cells.

Arachidonic Acids↗
PubMed2006

Mu and kappa opioid receptor agonists antagonize icilin-induced wet-dog shaking in rats.

Icilin is a cooling agent that precipitates vigorous wet-dog shakes in rats after acute i.p. administration. Recent research has emphasized the peripheral agonist properties (e.g. activation of transient receptor potential channels, TRPM8 and TRPA1) of icilin rather than its unusual and pronounced behavioral effects, often classified as quasi-morphine withdrawal. We tested selective opioid receptor agonists against icilin-induced wet-dog shakes in rats. Shaking was antagonized following s.c. pretreatment with the mu agonists, morphine (1, 2, 3 mg/kg) and buprenorphine (0.10 mg/kg) or the kappa agonists, nalfurafine (0.02, 0.04 mg/kg) and U50,488H (5 mg/kg). Pretreatment with ICI 204,448 (1, 5, 10 mg/kg), the peripherally directed kappa agonist, or the delta agonist, SNC 80 (0.30, 1, 3, 10 mg/kg), had no marked effect on the incidence of shaking. We conclude that (a) icilin can trigger shaking via interactions within the central nervous system and (b) mu and kappa opioid receptors are involved in suppressing this stimulant behavior.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed2004

TRPV2-immunoreactive intrinsic neurons in the rat intestine.

Transient receptor potential channel vanilloid subfamily 2 (TRPV2) was shown to receive noxious thermal stimuli (>52 degrees C), and to be expressed in fine myelinated afferent neurons. The mRNA and the immunoreactivity have also been detected in several peripheral tissues. We examined the expression of TRPV2 in the rat intestine. An analysis by transcriptase-polymerase chain reaction (RT-PCR) demonstrated TRPV2 gene expression in the intestine. Many TRPV2-positive neurons were observed in the myenteric plexus by immunohistochemistry. Some of these neurons were positive for calbindin D-28K (CaBP), which is present in intrinsic afferent neurons. TRPV2 immunoreactivity was also observed in nodose ganglion neurons (vagal afferents). These findings suggest that TRPV2 is expressed not only in sensory ganglion neurons, but also in enteric neurons, including primary afferent neurons.

Animals↗
PubMed2005

Hearing impairment in TRPV4 knockout mice.

Transient receptor potential channel vanilloid subfamily 4 (TRPV4), a member of TRP family, is a mechanosensitive non-selective cation channel. To investigate the role of TRPV4 in the cochlea, the hearing thresholds and effects of acoustic overexposure on the cochlea were examined in TRPV4 knockout mice. TRPV4 knockout mice at age 8 weeks exhibited normal, but those at 24 weeks revealed significantly higher thresholds by auditory brainstem response. The auditory threshold shift was significantly larger in the TRPV4 knockout than in the TRPV4+/+ mice 1 week after the acoustic overexposure of 128dB SPL. The present findings suggest that disruption of TRPV4 causes delayed-onset hearing loss and makes the cochlea vulnerable to acoustic injury.

Acoustic Stimulation↗
PubMed2006

Cellular localization of TRPC5 in the substantia nigra of rat.

Transient receptor potential channels (TRPC) are plasma membrane, non-selective cationic channels and have been proposed as candidates involved in the regulation of cellular Ca2+ influx. TRPC are involved in metabotropic glutamate receptor (mGluR)-mediated excitatory post-synaptic currents (EPSCs) in the dopaminergic neurons of the substantia nigra. We previously observed several subtypes of TRPC to be expressed at an mRNA level in the substantia nigra dopamine neurons. In particular, TRPC1 and TRPC5 are most frequently expressed in the substantia nigra. Our recent immunohistochemical findings showed that TRPC1 are mainly distributed in the dendrites of dopamine neurons. In the present study we have investigated, by means of immunohistochemistry and dual label immunofluorescence, the anatomical distribution of TRPC5 in the substantia nigra, and we have shown their preferential localization into the neuronal nuclei. Our findings suggest a role of TRPs in the calcium signaling system of the nucleus, although its physiological meaning needs further investigations.

Animals↗
PubMed2006

Numbing the senses: role of TRPA1 in mechanical and cold sensation.

In this issue of Neuron, Kwan et al. demonstrate that TRPA1 is critical for the transduction of noxious cold and mechanical stimuli, as well as in mediating the activation of nociceptors by endogenous and natural irritants. Differences between the present report and a previous study indicate that further study is needed to reach a consensus on the role of TRPA1 in the transduction of mechanical and noxious cold stimuli.

Animals↗
PubMed2006

The RNA binding and transport proteins staufen and fragile X mental retardation protein are expressed by rat primary afferent neurons and localize to peripheral and central axons.

Neuronal proteins have been traditionally viewed as being derived solely from the soma; however, accumulating evidence indicates that dendritic and axonal sites are capable of a more autonomous role in terms of new protein synthesis. Such extra-somal translation allows for more rapid, on-demand regulation of neuronal structure and function than would otherwise be possible. While mechanisms of dendritic RNA transport have been elucidated, it remains unclear how RNA is trafficked into the axon for this purpose. Primary afferent neurons of the dorsal root (DRG) and trigeminal (TG) ganglia have among the longest axons in the neuraxis and such axonal protein synthesis would be advantageous, given the greater time involved for protein trafficking to occur via axonal transport. Therefore, we hypothesized that these primary sensory neurons might express proteins involved in RNA transport. Rat DRG and TG neurons expressed staufen (stau) 1 and 2 (detected at the mRNA level) and stau2 and fragile x mental retardation protein (FMRP; detected at the protein level). Stau2 mRNA was also detected in human TG neurons. Stau2 and FMRP protein were localized to the sciatic nerve and dorsal roots by immunohistochemistry and to dorsal roots by Western blot. Stau2 and FMRP immunoreactivities colocalized with transient receptor potential channel type 1 immunoreactivity in sensory axons of the sciatic nerve and dorsal root, suggesting that these proteins are being transported into the peripheral and central terminals of nociceptive sensory axons. Based on these findings, we propose that stau2 and FMRP proteins are attractive candidates to subserve RNA transport in sensory neurons, linking somal transcriptional events to axonal translation.

Animals↗
PubMed2006

Effects of capsazepine on human small airway responsiveness unravel a novel class of bronchorelaxants.

Capsazepine is known as a transient receptor potential channel vanilloid subfamily 1 (TRPV(1)) antagonist that inhibits bronchoconstriction evoked in animals by TRPV(1) agonists. In this study, effects of capsazepine and chemically related analogues, so called capsazepinoids, were examined in vitro on contractile effects in human small airway preparations. Repeated cycles with 1h of LTD(4)-free physiological saline solution followed by 30min exposure to LTD(4) (10nM) demonstrated that the contractile responsiveness of the preparations exhibited little change over time despite repeated challenges (>12h). Capsazepine (1-100microM) reversibly and concentration-dependently inhibited the contractile response to LTD(4) with EC(50) approximately 10microM and approximately 90% relaxation at 100microM. Capsazepine (10microM) was approximately equally effective to attenuate the contractions evoked by several different inflammatory contractile agonists (LTD(4), PGD(2), histamine), and it relaxed preparations with established tonic contraction due to LTD(4). Higher concentrations of capsazepine were needed to relax ACh-contractions. The effect of capsazepine on LTD(4)-induced contractions was not significantly reduced by pre-treating the preparations with either of propranolol (10microM)+atropine (1microM), L-NAME (1mM), indomethacin (1microM), iberiotoxin (0.1microM), capsaicin (10microM), and nifedipine (10microM). Although the mechanism of action of the present capsazepine-induced bronchorelaxation remains unknown it emerged here that they represent a generally effective principle exerting a functional antagonism against contractile mediators but distinct from beta receptor agonists and inhibitors of L-type calcium channels. The inhibitory effect of capsazepine is shared by chemical analogues, but not with other TRPV(1) antagonists, suggesting the possibility that capsazepine represents a novel class of bronchorelaxants effective in human small airways. These findings were not predicted by previous observations that have concerned quite limited effects of capsazepine on airway tone in different animal test systems. If potency can be further increased and the results translated to in vivo, compounds representing the capsazepinoid class of bronchorelaxants might become useful in the treatment of patients suffering from asthma and COPD.

Acetylcholine↗
PubMed2006

Analgesic strategies beyond the inhibition of cyclooxygenases.

Blocking the formation of prostaglandins with cyclooxygenase (COX) inhibitors has been the treatment of choice for inflammatory pain for more than a century. Although these agents provide profound pain relief, their long-term use is hampered by severe side-effects, mainly ulceration of the upper gastrointestinal tract. The development of COX-2-selective inhibitors ("coxibs") has significantly reduced gastrointestinal toxicity, but evidence from controlled clinical trials and experimental studies indicates that the use of coxibs has a significant cardiovascular risk. Recently, signalling elements downstream of COX-2 inhibition have been identified, which offer a great diversity of possible targets. This review focuses on prostaglandin E synthases, prostaglandin receptors and downstream effectors of prostaglandins in the PNS and CNS, including transient receptor potential channels, tetrodotoxin-resistant Na(+) channels and inhibitory glycine receptors. These novel targets should enable inflammatory pain to be treated with improved specificity and, possibly, fewer side-effects.

Cyclooxygenase Inhibitors↗
PubMed2006

Basis of lethality in C. elegans lacking CUP-5, the Mucolipidosis Type IV orthologue.

Mutations in MCOLN1, which encodes the protein h-mucolipin-1, result in the lysosomal storage disease Mucolipidosis Type IV. Studies on CUP-5, the human orthologue of h-mucolipin-1 in Caenorhabditis elegans, have shown that these proteins are required for lysosome biogenesis. We show here that the lethality in cup-5 mutant worms is due to two defects, starvation of embryonic cells and general developmental defects. Starvation leads to apoptosis through a CED-3-mediated pathway. We also show that providing worms with a lipid-soluble metabolite partially rescues the embryonic lethality but has no effect on the developmental defects, the major cause of the lethality. These results indicate that supplementing the metabolic deficiency of Mucolipidosis Type IV patients mat not be sufficient to alleviate the symptoms due to tissue degeneration.

Adenosine Triphosphate↗
PubMed2005

Neuregulin-regulated gene expression in mammary carcinoma cells.

Recent studies have suggested that autocrine production of Neuregulin (NRG), a growth factor that activates members of the Epidermal Growth Factor Receptor/ErbB family of proto-oncogenes, is sufficient for breast tumor initiation and progression. To elucidate the molecular mechanisms regulating these events, we undertook a global analysis of genes regulated by NRG in luminal mammary epithelial cell lines. Gene expression profiling of estrogen receptor-positive T47D cells exposed to NRG-1 revealed both previously identified and novel targets of NRG activation. Profiling of other estrogen receptor-positive breast cancer cell lines, MCF7 and SUM44, yielded a group of twenty-one genes whose transcripts are upregulated by NRG in all three lines tested. The NRG targets are FBJ murine osteosarcoma viral oncogene homolog B, Early growth response 1, v-jun avian sarcoma virus 17 oncogene homolog, Activating transcription factor 3, Homo sapiens cDNA FLJ31636 fis, Jun B proto-oncogene, Forkhead box C1, Platelet/endothelial cell adhesion molecule 1, NADPH-dependent retinol dehydrogenase/reductase, Dual specificity phosphatase 5, NGF inducible protein TIS21, Connective tissue growth factor, Jun D proto-oncogene, Serum response factor, Cullin 1, v-myc avian myelocytomatosis viral oncogene, Transient receptor potential channel 1, Low density lipoprotein receptor, Transforming growth factor beta 1, Nucleoporin 88 kDa, and Pleckstrin homology-like domain A1. Since NRG activation of these cells induces resistance to anti-hormonal therapy, the identified genes may provide clues to molecular events regulating mammary tumor progression and hormone independence.

Breast Neoplasms↗
PubMed2006

Identification and characterization of GSRP-56, a novel Golgi-localized spectrin repeat-containing protein.

Spectrin repeat (SR)-containing proteins are important for regulation of integrity of biomembranes, not only the plasma membrane but also those of intracellular organelles, such as the Golgi, nucleus, endo/lysosomes, and synaptic vesicles. We identified a novel SR-containing protein, named GSRP-56 (Golgi-localized SR-containing protein-56), by a yeast two-hybrid method, using a member of the transient receptor potential channel family, TRPV2, as bait. GSRP-56 is an isoform derived from a giant SR-containing protein, Syne-1 (synaptic nuclear envelope protein-1, also referred to as Nesprin-1 or Enaptin), predicted to be produced by alternative splicing. Immunological analysis demonstrated that this isoform is a 56-kDa protein, which is localized predominantly in the Golgi apparatus in cardiomyocytes and C2C12 myoblasts/myotubes, and we found that two SR domains were required both for Golgi targeting and for interaction with TRPV2. Interestingly, overexpression of GSRP-56 resulted in a morphological change in the Golgi structure, characterized by its enlargement of cis-Golgi marker antibody-staining area, which would result partly from fragmentation of Golgi membranes. Our findings indicate that GSRP-56 is a novel, particularly small Golgi-localized member of the spectrin family, which possibly play a role in maintenance of the Golgi structure.

Animals↗
PubMed2002

Ca(2+)-calmodulin regulates receptor-operated Ca(2+) entry activity of TRPC6 in HEK-293 cells.

Mammalian homologues of the Drosophila transient receptor potential channel (TRPC) are involved in Ca(2+) entry following agonist stimulation of nonexcitable cells. Seven mammalian TRPCs have been cloned but their mechanisms of activation and/or regulation are still the subject of intense research efforts. It has already been shown that calmodulin (CaM) can regulate the activity of Drosophila TRP and TRPL and, more recently, CaM has been shown to interact with mammalian TRPCs. In this study, TRPC6 stably transfected into HEK-293 cells was used to investigate the possible influence of CaM on TRPC6-dependent Ca(2+) entry. Overexpression of TRPC6 in mammalian cells is known to enhance agonist-induced Ca(2+) entry, but not thapsigargin-induced Ca(2+) entry. Here, we show that CaM inhibitors (calmidazolium and trifluoperazine) abolish receptor-operated Ca(2+) entry (ROCE) without affecting thapsigargin-operated Ca(2+) entry and that the activity of CaM is dependent on complexation with Ca(2+). We also show that Ca(2+)-CaM binds to TRPC6 and that the binding can be abolished by CaM inhibitors. These results indicate that CaM is involved in the modulation of ROCE.

Calcium↗
PubMed2003

Cold transduction in rat trigeminal ganglia neurons in vitro.

Three sub-populations of sensory neurons may be distinguished based on responses to a decrease in temperature: one has a relatively low threshold for activation (cool fibers), a second has a high threshold for activation (cold nociceptors), and the third is unresponsive to a decrease in temperature. Results from several recent studies suggest that the ability to detect a decrease in temperature reflects an intrinsic property(ies) of sensory neurons and therefore may be characterized via the study of the sensory neuron cell body in vitro. However, while three unique ionic mechanisms of cold transduction have recently been identified (i.e. activation of the transient receptor potential channel M8 [TRPM8] or an epithelial Na(+) channel [ENaC] or inhibition of two pore K(+) channel [TREK-1]), the possibility that these "mechanisms" may be differentially distributed among sensory neurons in a manner consistent with predictions based on in vivo observations has not been investigated. To investigate this possibility, we have characterized the influence of cooling on isolated trigeminal ganglion (TG) neurons from adult rats in vitro with Ca(2+) microfluorimetry in combination with a series of pharmacological interventions. We report that neurons responded to a decrease in temperature from approximately 34 degrees C to approximately 12 degrees C in one of two ways: 1) with a low threshold (30.1+/-0.6 degrees C) for activation demonstrating an increase in fluorescence with a minimal decrease in bath temperature (12.3%); 2) with a high threshold for activation (21.5+/-0.6 degrees C), demonstrating an increase in fluorescence only after a substantial decrease in bath temperature (13.3%); 74.4% did not respond to a decrease in temperature with an increase [Ca(2+)](i). These responses also were distinguishable on the basis of their rate of activation and degree of desensitization in response to prolonged application of a cold stimulus: low threshold responses were associated with a rapid (tau=12.0+/-5.7 s) increase in [Ca(2+)](i) and a time constant of desensitization of 85.8+/-20.7 s while high threshold responses were associated with a slow (tau=38.1+/-8.2 s) increase in [Ca(2+)](i) and demonstrated little desensitization over 4 min of stimulation. We refer to low threshold and high threshold cold responsive TG neurons as LT(cool) and HT(cool) neurons, respectively. LT(cool) and HT(cool) neurons were distributed among two distinct subpopulations of TG neurons distinguishable on the basis of cell body size and isolectin B4 staining. Both ENaC and TRPM8 appear to contribute to cold transduction, but neither is sufficient to account for all aspects of cold transduction in either population of TG neurons. Furthermore, inhibition of Ba(2+) and/or Gd(3+) sensitive two-pore K(+) channels (i.e. TREK-1 and TRAAK) was insufficient to account for cold transduction in HT(cool) or LT(cool) neurons. Our results suggest that cold transduction in sensory neurons is a complex process involving the activation and inhibition of several different ion channels. In addition, there appear to be both similarities and differences between mechanisms underlying cold transduction in LT(cool) and HT(cool) neurons. Identification of specific mechanisms underlying cold transduction in LT(cool) and HT(cool) neurons may enable the development of novel therapeutic interventions for the treatment of pathological conditions such as cold allodynia.

Animals↗
PubMed2000

Constitutive activity of the light-sensitive channels TRP and TRPL in the Drosophila diacylglycerol kinase mutant, rdgA.

Mutations in the Drosophila retinal degeneration A (rdgA) gene, which encodes diacylglycerol kinase (DGK), result in early onset retinal degeneration and blindness. Whole-cell recordings revealed that light-sensitive Ca2+ channels encoded by the trp gene were constitutively active in rdgA photoreceptors. Early degeneration was rescued in rdgA;trp double mutants, lacking TRP channels; however, the less Ca2+-permeable light-sensitive channels (TRPL) were constitutively active instead. No constitutive activity was seen in rdgA;trpI;trp mutants lacking both classes of channel, although, like rdgA;trp, these still showed a residual slow degeneration. Responses to light were restored in rdgA;trp but deactivated abnormally slowly, indicating that DGK is required for response termination. The findings suggest that early degeneration in rdgA is caused by uncontrolled Ca2+ influx and support the proposal that diacylglycerol or its metabolites are messengers of excitation in Drosophila photoreceptors.

Animals↗