B Nilius

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

..This review summarizes data on TRPV4 as a paradigm of gating diversity in this subfamily of Ca2+ entry channels...

..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...

..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...

..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...

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

..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...

..Bernstein, the first detailed description of the conductance properties of excitable tissues by L. Hermann, and more recently the publication of the patch-clamp method by E. Neher and B. Sakmann...

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

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

..In conclusion, we have identified two domains in the carboxyl terminus of ECaC1 that control Ca(2+)-dependent inactivation...

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

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..In conclusion, the TM2-TM3 loop is a critical determinant of the inactivation in ECaC1 and ECaC2...

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..Spermine blocked TRPM4 currents with an IC(50) of 61 microM. In conclusion, TRPM4 is a channel that can be effectively modulated by intracellular nucleotides and polyamines...

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

..Hopefully, a better understanding of TRP channel physiology will provide important insight into the relationship between TRP channel dysfunction and human diseases...

..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...

..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...

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

..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...

..These results indicate that the C-terminus of TRPM4 is critically involved in mediating the DV effects. In conclusion, decavanadate modulates TRPM4, but not TRPM5, by inhibiting voltage-dependent closure of the channel...

..Thus, the Ca(2+) sensitivity of TRPM4 is regulated by ATP, PKC-dependent phosphorylation, and calmodulin binding at the C terminus...

..This perspective summarizes problems in identifying SOCs, suggests approaches to solving these problems, and discusses concerns over the current tendency to focus exclusively on the hypothesis that TRPCs comprise SOCs...

..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)...

..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...

..It is concluded that water permeates VRAC and might be able to accelerate water transport by providing an additional permeation pathway for water. Therefore VRAC can be considered as a water-permeable, "wet" channel...

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

..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...

..An understanding of the genetics of disease may lead to the development of targeted new therapies...

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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...

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

..6. It is concluded that hTRP3 forms non-selective plasmalemmal cation channels that function as a pathway for agonist-induced Ca2+ influx...

..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...

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..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...

..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)...

..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...

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

..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...

..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...

..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...

..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...

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..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...

..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...

..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...

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

..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...

..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...

..In contrast, expression of ClC-6c is more restricted, since it was only detected in kidney...

..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...

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

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

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

..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...

..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...

..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...

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

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

..HGF/SF increases Ca(2+) entry via TRPV1, but not via TRPV4. This rise in [Ca(2+)](i) may constitute an early response of a signalling cascade that gives rise to cell locomotion and the migratory phenotype...

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..Activation of TRPV4 in vascular endothelial cells might therefore contribute to the relaxant effects of endocannabinoids and their P450 epoxygenase-dependent metabolites on vascular tone...

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

..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...

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

..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...

..It is therefore concluded that caveolin-1 facilitates the hypotonicity-induced release of Cl(-), taurine, and ATP, and that in polarized epithelial cells, the effect of caveolin-1 is compartmentalized to the basolateral membrane...

..Thus, in JME/CF15 cells inhibition of the ENaC function by chronic incubation with EGF is a Ca(2+)-mediated process that affects trafficking and surface expression of ENaC channels...

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

..It is concluded that the Ca(2+)-activated non-selective action channel in EA cells is modulated by the metabolic state of the cell and by NO...

..Two mutations, H620Q and A800G, resulted in increased intrinsic chloride transport activities. Finally, T665S and E826K CFTR had single channel properties not significantly different from wild-type CFTR...

..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...

..We conclude that Kv1.1 and Kir2.1 alpha-subunit proteins fail to assemble and do not contribute functional diversity to K+ channels...

..Autonomous contractile activity (ACA) is a well-known phenomenon in isolated bladders from different species and seems to be important in the physiology of both normal and dysfunctional voiding...

..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...

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

..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...

..As a consequence, glucose-induced insulin release from Trpm5(-/-) pancreatic islets is significantly reduced, resulting in an impaired glucose tolerance in Trpm5(-/-) mice...

..Certainly, more structure-function studies are needed for a better understanding of T-type channel physiology and the rational design of treatments against T-type channel-related pathologies...

..Here we explored the behavior of stretch-induced contractile activity (SIC) and its muscarinic regulation in neonatal and adult rat bladders...

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..Activation of TRP channels is highly sensitive to a variety of chemical and physical stimuli, allowing them to function as dedicated biological sensors that are essential in processes such as vision, taste, tactile sensation and hearing...

..We conclude that the pore of TRPA1 is dynamic and supports a surprisingly large Ca(2+) influx...

..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...

..This indicated that repression of CFTR by MDR1 induction requires the presence of the native CFTR promoter...

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

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..Thus, Y16, Y362, Y363 and Y370 are required for the appropriate three-dimensional structure and function of the intracellular P2X(1) domains...

..Our data indicate that TRPM6 comprises all or part of the apical Mg2+ channel of Mg2+-absorbing epithelia...

..In conclusions, our data demonstrated that expression of truncated CFTR constructs could be a novel promising approach to improve maturation of DeltaF508-CFTR channels...

..However, the selectivity filter of TRPV6 is wider than that of K(+) channels and lined by amino acid side chains rather than main chain carbonyls...