B Nilius

..This review gives an overview of available experimental and theoretical data and discusses the functional impact of pore-structure modifications on TRP channel properties...

..Putative mechanisms to explain the puzzle, and how mutations in the same region of the channel cause different diseases, are discussed and experimental approaches to tackle this surprising problem are suggested...

..Moreover, its role in the (patho)physiology of nearly all organ systems is anticipated, and will be discussed along with the potential of TRPA1 as a drug target for the management of various pathological conditions...

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..A PIP(2)-binding pocket seems to comprise a part of the TRP domain and especially pleckstrin homology domains in the C-terminus...

..In this review, we provide an overview of the impact of TRP channels on the pathogenesis of several diseases and identify several TRPs for which a causal pathogenic role might be anticipated...

..Finally, an overview is given how research on T-type Ca2+ channels has developed in the last years and in which topics it is branching out, a process, which is still ongoing...

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..Finally, the role of TRPs will be discussed in neuronal diseases and neurodegenerative disorders...

..A functional hallmark of TRPM4, as for several TRP channels, is a dramatic shift of its voltage dependence towards negative, physiologically meaningful potentials...

..In this review, we summarize current knowledge about the mechanisms of interaction between TRP channels and PIPs, and discuss the possible functional implications of TRP-PIP interactions to human physiology and pathophysiology...

..Finally, TRP channels will become important novel pharmacological targets for the treatment of human diseases and for modulation of sensory functions, e.g. the perception of flavor...

..A surprising functional association between TRPM3, a mysterious member of the family of transient receptor potential (TRP) cation channels, and the sulphated version of pregnenolone, 'mother' of all steroid hormones, has been identified...

..In this issue of Cell, Sharif-Naeini et al. (2009) show that a candidate mechanosensing channel, TRPP2 (PKD2), unexpectedly acts as an inhibitor of a still-elusive stretch-activated cation channel in vascular smooth muscle cells...

..Based on available genetic indications, we will also describe several putative pathological conditions in which (mal)function of TRP channels could be anticipated...

..Finally, we assess some problems inherent to activation of TRPA1 by the reaction of electrophilic compounds with the nucleophilic thiol sink of N-terminal reactive cysteines...

..8. It is concluded that [Ca2+]i activates small-conductance Cl- channels in endothelial cells, which coexist with the volume-activated Cl- channels described previously...

..7. It is concluded that a reduction of gamma 1 activates an anion current that is identical to that activated by cell swelling. Changes in intracellular ionic strength may shift the volume set point for activation of ICl,swell...

..It is concluded that the permeation profile of ECaC for monovalent cations suggests a strong field-strength binding site that may be involved in Ca2+ permeation and Mg2+ block...

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..We therefore conclude that the interaction between caveolin-1 and detergent-resistant lipid rafts is an important prerequisite for endothelial VRAC activity...

..9. These experiments provide strong evidence that the Rho-Rho kinase pathway is involved in the VRAC activation cascade...

..HCO3- and lactate permeation, as well as the up-regulation of VRAC at an acidic intracellular pH might be related to a possible role of this channel in cellular pH regulation...

..We conclude that mibefradil has potent blocking effects on Ca2+ channels in mammalian motoneurones. We hypothesize that therapeutic and pharmacological effects of mibefradil may involve actions on Ca2+ channels other than type T...

..It is concluded that the C-terminal part of the R-domain is an important determinant for CFTR-CaCC interaction...

..From the structural information of the calixarenes, we estimate a lower and upper limit of 11*12 and 17*12 A2 respectively for the cross-sectional area of the pore...

..Slow recovery seems to depend on dissociation of Ca( 2+ from an internal Ca2+ binding site at ECaC...

..We conclude that CPAE cells do not express voltage-gated (ClC-type) or cAMP-gated (CFTR-type) Cl- channels, but activate large Cl- currents after volume (mechanical?) or chemical (Ca2+) stimulation...

..RT-PCR experiments did not provide any evidence that the endothelial Ca(2+)-activated Cl- channel might be identical with a recently cloned Ca(2+)-sensitive Cl- channel (CaCC)...

..We conclude that annexin II-p11 complex formation is either directly or indirectly involved in the activation of ICl, vol in endothelial cells...

..The failure to activate TRPV4 channels by heat in inside-out patches, which responded to 4alphaPDD, may indicate that heat activation depends on the presence of an endogenous ligand, which is missing in inside-out patches...

..The second part concentrates on the Rho/Rho kinase/myosin phosphorylation cascade and on compartmentalization in caveolae as modulators of the signal transduction cascade that controls VRAC gating in vascular endothelial cells...

..4 and 38 +/- 4 microM (n = 8) at pH 8.5. The affinity of ECaC for Ca2+ was also affected by extracellular pH, shifting from 4.8 +/- 0.7 microM (n = 6) at pH 6.0 to 161 +/- 30 nM (n = 5) at pH 7.4 and 425 +/- 117 nM (n = 8) at pH 8.5...

..The c-kit receptor expressed by interstitial cells in the gastrointestinal tract is crucial to their pacemaking function. The function of similar c-kit-expressing myometrial cells is unknown...

..This study describes the functional interaction between the putative Ca2+ channel TRP4 and the cystic fibrosis transmembrane conductance regulator, CFTR, in mouse aorta endothelium (MAEC)...

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..Conversely, NIPP1(191-210), an MLCP inhibitory peptide, potentiated the activation of VRAC by a 25% hypotonic stimulus. These data indicate that activation of VRAC is modulated by MLC phosphorylation...

..This review summarizes the currently available information concerning members of the TRP family expressed in mammalian tissues...

..Finally, we discuss the role of Cl- channels in various diseases and describe the pathological phenotypes observed in knockout mice models...

..Taken together, these results suggest that the MDR1 linker domain can substitute for part of the regulatory domain of the CFTR protein...

..The kinetic and pharmacological profile of VRAC and TRP12 currents were also different...

..Our results imply that the pores of CaT1 and CRAC are not identical and indicate that CaT1 is a Mg(2+)-gated channel not directly related to CRAC...

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..Finally, cold plate and tail-flick experiments reveal TRPA1-dependent, cold-induced nociceptive behavior in mice. We conclude that TRPA1 acts as a major sensor for noxious cold...

..These results indicate that P2Y2 receptors linked to intracellular Ca2+ mobilization are present in human vascular endothelial cells. The initial [Ca2+]i mobilization is followed by a phase of elevated [Ca2+]i influx...

..The inhibition by clomiphene is not stereoselective and occurs at concentrations close to therapeutically relevant concentrations. Finally, both drugs inhibit the proliferation of endothelial cells...

..Instead, they are in complete agreement with a model in which a decrease of Gammai rather than an increase in cell volume is the initial trigger for activation of ICl,swell...

..This review summarizes and discusses the current knowledge on the TRP protein structure and its impact on the regulation of the channel function...

..In some instances, disease-causing mutations or abnormalities provide us with new insights into the cell biology of the various Ca(2+)transporters...

..Mutations of two neighboring negatively charged residues, i.e. Glu(535) and Asp(550), had only minor effects on Ca(2+) permeation properties...

..We therefore conclude that c-Src-mediated inhibition of VRAC requires compartmentalization of c-Src to caveolae and that the Src homology domains 2 and/or 3 are necessary and sufficient for inhibition...

..6 It is concluded that blockade of volume-activated Cl- currents by extracellular sodium cromoglycatemay be due to an intracellular action following its permeation across the cell membrane...

..Phorbol esters and heat operate by means of a distinct, PLA(2)- and cytochrome p450 epoxygenase-independent pathway, which critically depends on an aromatic residue at the N terminus of the third transmembrane domain...

..4. Molecular candidates for this channel (i.e. ClC-2, a member of the ClC-family of voltage-dependent Cl- channels, the mdr-1 encoded P-glycoprotein, the nucleotide-sensitive pICln protein and phospholemman) will be discussed...

..Evidence that they belong to the class of P-glycoprotein associated Cl--channels is however only marginal, whereas their biophysical characteristics differ significantly from those of the CIC-2 volume-activated Cl--channels...

..The mutation of both divergent aspartates only partially confers HVA channel permeation properties to the alpha(1G) Ca(2+) channel subunit...

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..Such polyvariant mutant genes could explain why apparently normal CFTR genes cause disease. Moreover, they might be responsible for variation in the phenotypic expression of CFTR mutations, and be of relevance in other genetic diseases...

..C-kit receptor expressing interstitial cells generate and coordinate the electrical signals that control peristalsis in the gut. However, the function of interstitial cells in the myometrium is not known...

..Our results suggest a simple unifying principle that explains both cold and heat sensitivity in TRP channels...

..Together, our data establish that CYP-derived EETs modulate the activity of TRPV4 channels in endothelial cells and shows the unraveling of novel modulatory pathways via CYP2C modulation and sEH inhibition...

..We conclude that VRAC block is a general property of this pharmacological class of selective serotonin reuptake inhibitors...

..Thus, phenotypic differences in combination with RT-PCR data point to the existence of different molecular species for Ca(2+)-activated Cl- channels...

..Voltage dependence of TRPM4 may be functionally important, especially in excitable tissues generating plateau-like or bursting action potentials...

..We concluded that the phorbol derivatives activate TRPV4 (VR-OAC, VRL-2, OTRPC4, TRP12) independently from protein kinase C, in a manner consistent with direct agonist gating of the channel...

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..TRPM4 displayed a 10-fold higher affinity for block by flufenamic acid. Importantly, ATP4- blocked TRPM4 with high affinity (IC50 of 0.8+/-0.1 microM), whereas TRPM5 is insensitive to ATP4- at concentrations up to 1 mM...

..Our data demonstrate that PIP2 is a strong positive modulator of TRPM4, and implicate the C-terminal PH domain in PIP2 action. PLC-mediated PIP2 breakdown may constitute a physiologically important brake on TRPM4 activity...

..The effects of intracellular Mg(2+) on TRPV6 are partially reminiscent of the gating mechanism of inwardly rectifying K(+) channels and may represent a novel regulatory mechanism for TRPV6 function in vivo...

..Together, our results identify TRP channels in sensory neurons as molecular targets of CLT, and offer means to develop novel CLT preparations with fewer unwanted sensory side effects...

..These changes are independent of the alterations of the selectivity properties and channel protonation...

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..The functional impact of VRAC as a possible mechano-sensor in endothelium and as a regulatory component in the cell cycle, endothelial cell proliferation and possible angiogenesis will be discussed...

..The role of the calcium-conducting ion channel transient receptor potential canonical 6 (TRPC6) in macrophage inflammatory protein-2 (MIP-2) induced migration of mouse neutrophils was investigated...

..Controversial data regarding the expression pattern and the potential impact of TRP channels in prostate function, and their involvement in prostate cancer and other prostate diseases, will be discussed...

..Finally, aequorin-based measurements demonstrate that the TRPM8-independent menthol-induced Ca2+ release originates from both endoplasmic reticulum and Golgi compartments...

..Thus, our results suggest that TRPM4 is critically involved in migration of BMMCs by regulation of Ca(2+)-dependent actin cytoskeleton rearrangements...

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..Our results establish the physiological function of TRPM4 channels as critical regulators of Ca(2+) entry in mast cells...

..Based on these findings, we present a Monod-Wyman-Changeux-type model explaining the combined effects of voltage, temperature and menthol on TRPM8 gating...

..These channels may contribute to the (mechano)sensory function of the urothelial layer and represent potential targets for the treatment of bladder dysfunction...

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..Taken together, these data suggest that PACSIN 3 acts as an auxiliary protein of TRPV4 channel that not only affects the channel's subcellular localization but also modulates its function in a stimulus-specific manner...

..In conclusion, we think that the use of negative controls on knockout mice, whenever available, is mandatory when conducting immunohistochemical localization studies...

..These results represent the first description of the effects of surface charge screening on a TRP channel and provide a straightforward explanation for the known effects of extracellular Ca(2+) on cold-sensitive neurons...

..The inhibition of TRPM5 by bitter compounds constitutes the molecular basis of a novel mechanism of taste interactions, whereby the bitter tastant inhibits directly the sweet transduction pathway...

..The identification of TRPA1 as a nicotine target suggests that existing models of nicotine-induced irritation should be revised and may facilitate the development of smoking cessation therapies with less adverse effects...

..These data demonstrate a previously unrecognized role for TRPV4 in voiding behavior, raising the possibility that TRPV4 plays a critical role in urothelium-mediated transduction of intravesical mechanical pressure...

..1. Our results indicate that common structures, most likely the S6 transmembrane segments, are involved in the conformational changes occurring during both channel activation and inactivation...

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..Our findings delineate the selectivity filter of TRPM channels and provide the first insight into the molecular basis of monovalent cation selectivity...

..Our findings delineate the pore region of TRPV4 and give a first insight into the possible architecture of its permeation pathway...

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..Possible functional roles of this channel will be correlated with its observed expression pattern. Finally, we discuss the structural determinants of TRPV4 channel function...

..Regulation of channel availability by interaction with a protein bound to a site at the C-terminus of both channels will be demonstrated. Functional consequences of these different mechanisms of gating will be discussed...

..Some structural considerations will be given indicating that, although the voltage sensor is not yet known, the C-terminus may substantially change the voltage dependence of these channels...

..In this review we discuss recent evidence that implicates members of the TRP superfamily in sensory signal transduction...

..Taken together, our results demonstrate that TRPP3, on its own, can act as a voltage-dependent, pH- and volume-sensitive plasma membrane cation channel...