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111.
Zhaobing Gao Tangzhi Zhang Meng Wu Qiaojie Xiong Haiyan Sun Yinan Zhang Liansuo Zu Wei Wang Min Li 《The Journal of biological chemistry》2010,285(36):28322-28332
Kv7 channels, especially Kv7.2 (KCNQ2) and Kv7.3 (KCNQ3), are key determinants for membrane excitability in the brain. Some chemical modulators of KCNQ channels are in development for use as anti-epileptic drugs, such as retigabine (D-23129, N-(2-amino-4-(4-fluorobenzylamino)-phenyl)), which was recently approved for clinical use. In addition, several other compounds were also reported to potentiate activity of the Kv7 channels. It is therefore of interest to investigate compound-channel interactions, so that more insights may be gained to aid future development of therapeutics. We have conducted a screen of 20,000 compounds for KCNQ2 potentiators using rubidium flux combined with atomic absorption spectrometry. Here, we report the characterization of a series of new structures that display isoform specificity and induce a marked reduction of deactivation distinct from that of retigabine. Furthermore, KCNQ2(W236L), a previously reported mutation that abolishes sensitivity to retigabine, remains fully sensitive to these compounds. This result, together with mutagenesis and other studies, suggests that the reported compounds confer a unique mode of action and involve new molecular determinants on the channel protein, consistent with the idea of recognizing a new site on channel protein. 相似文献
112.
Dunkel Marcel 《FEBS letters》2010,584(11):2433-2439
Vacuolar tandem-pore channels could not be analysed in Xenopus oocytes so far, due to misguided translocation. Owing to the conservation of their pore regions, we were able to prepare functional pore-chimeras between the plasma membrane localised TPK4 and vacuolar TPKs. Thereby, we found evidence that TPK2, TPK3 and TPK5, just like TPK4, form potassium-selective channels with instantaneous current kinetics. Homology modelling and mutational analyses identified a pore-located aspartate residue (Asp110), which is involved in potassium permeation as well as in inward rectification of TPK4. Furthermore, dominant-negative mutations in the selectivity filter of either pore one or two (Asp86, Asp200) rendered TPK4 non-functional. This observation supports the notion that the functional TPK4 channel complex is formed by two subunits. 相似文献
113.
Inanobe A Nakagawa A Matsuura T Kurachi Y 《The Journal of biological chemistry》2010,285(49):38517-38523
Inward rectifier K(+) (Kir) channels are activated by phosphatidylinositol-(4,5)-bisphosphate (PIP(2)), but G protein-gated Kir (K(G)) channels further require either G protein βγ subunits (Gβγ) or intracellular Na(+) for their activation. To reveal the mechanism(s) underlying this regulation, we compared the crystal structures of the cytoplasmic domain of K(G) channel subunit Kir3.2 obtained in the presence and the absence of Na(+). The Na(+)-free Kir3.2, but not the Na(+)-plus Kir3.2, possessed an ionic bond connecting the N terminus and the CD loop of the C terminus. Functional analyses revealed that the ionic bond between His-69 on the N terminus and Asp-228 on the CD loop, which are known to be critically involved in Gβγ- and Na(+)-dependent activation, lowered PIP(2) sensitivity. The conservation of these residues within the K(G) channel family indicates that the ionic bond is a character that maintains the channels in a closed state by controlling the PIP(2) sensitivity. 相似文献
114.
Srikant Rangaraju Keith K. Khoo Zhi-Ping Feng George Crossley Daniel Nugent Ilya Khaytin Victor Chi Cory Pham Peter Calabresi Michael W. Pennington Raymond S. Norton K. George Chandy 《The Journal of biological chemistry》2010,285(12):9124-9136
Peptide toxins found in a wide array of venoms block K+ channels, causing profound physiological and pathological effects. Here we describe the first functional K+ channel-blocking toxin domain in a mammalian protein. MMP23 (matrix metalloprotease 23) contains a domain (MMP23TxD) that is evolutionarily related to peptide toxins from sea anemones. MMP23TxD shows close structural similarity to the sea anemone toxins BgK and ShK. Moreover, this domain blocks K+ channels in the nanomolar to low micromolar range (Kv1.6 > Kv1.3 > Kv1.1 = Kv3.2 > Kv1.4, in decreasing order of potency) while sparing other K+ channels (Kv1.2, Kv1.5, Kv1.7, and KCa3.1). Full-length MMP23 suppresses K+ channels by co-localizing with and trapping MMP23TxD-sensitive channels in the ER. Our results provide clues to the structure and function of the vast family of proteins that contain domains related to sea anemone toxins. Evolutionary pressure to maintain a channel-modulatory function may contribute to the conservation of this domain throughout the plant and animal kingdoms. 相似文献
115.
Overview This review considers the “tween twixt and twain” of hair cell physiology, specifically the signaling elements and membrane
conductances which underpin forward and reverse transduction at the input stage of hair cell function and neurotransmitter
release at the output stage. Other sections of this review series outline the advances which have been made in understanding
the molecular physiology of mechanoelectrical transduction and outer hair cell electromotility. Here we outline the contributions
of a considerable array of ion channels and receptor signaling pathways that define the biophysical status of the sensory
hair cells, contributing to hair cell development and subsequently defining the operational condition of the hair cells across
the broad dynamic range of physiological function. 相似文献
116.
Vitamins C and E Modulate Neuronal Potassium Currents 总被引:1,自引:0,他引:1
We investigated the effects of vitamins C and E on the delayed-rectifier potassium current (IKDR), which is important in repolarizing the membrane potential, and on the transient A-type potassium current (IKA), which regulates neuronal firing frequency. The whole-cell patch-clamp technique was used to measure the currents from cultured
Drosophila neurons derived from embryonic neuroblasts. The membrane potential was stepped to different voltages between −40 and +60
mV from a holding potential of −80 mV. IKDR and IKA measured in the vitamin C-containing solution (IKDR 305 ± 16 pA, IKA 11 ± 2 pA) were smaller than those measured in the control solution (488 ± 21 pA, IKA 28 ± 3 pA). By contrast, IKDR and IKA measured in the vitamin E-containing solution (IKDR 561 ± 21 pA, IKA 31 ± 3 pA) were greater than those measured in the control solution (422 ± 15 pA, 17 ± 2 pA). These results indicate that
vitamins C and E can modulate potassium current amplitudes and possibly lead to altered neuronal excitability. 相似文献
117.
Na+/K+-ATPase plays a key role in the transport of Na+ throughout the nephron, but ageing appears to be accompanied by changes in the regulation and localization of the pump. In
the present study, we examined the effect of in vitro cell ageing on the transport of Na+ and K+ ions in opossum kidney (OK) cells in culture. Cells were aged by repeated passing, and Na+/K+-ATPase activity and K+ conductance were evaluated using electrophysiological methods. Na+K+-ATPase α1– and β1-subunit expression was quantified by Western blot techniques. Na+/H+ exchanger activity, changes in membrane potential, cell viability, hydrogen peroxide production and cellular proliferation
were determined using fluorimetric assays. In vitro cell ageing is accompanied by an increase in transepithelial Na+ transport, which results from an increase in the number of Na+/K+-ATPase α1- and β1-subunits, in the membrane. Increases in Na+/K+-ATPase activity were accompanied by increases in K+ conductance as a result of functional coupling between Na+/K+-ATPase and basolateral K+ channels. Cell depolarization induced by both KCl and ouabain was more pronounced in aged cells. No changes in Na+/H+ exchanger activity were observed. H2O2 production was increased in aged cells, but exposure for 5 days to 1 and 10 μM of H2O2 had no effect on Na+/K+-ATPase expression. Ouabain (100 nM) increased α1-subunit, but not β1-subunit, Na+/K+-ATPase expression in aged cells only. These cells constitute an interesting model for the study of renal epithelial cell
ageing. 相似文献
118.
Chromaffin granules are involved in catecholamine synthesis and traffic in the adrenal glands. The transporting membrane proteins
of chromaffin granules play an important role in the ion homeostasis of these organelles. In this study, we characterized
components of the electrogenic 86Rb+ flux observed in isolated chromaffin granules. In order to study single channel activity, chromaffin granules from the bovine
adrenal medulla were incorporated into planar lipid bilayers. Four types of cationic channel were found, each with a different
conductance. The unitary conductances of the potassium channels are 360 ± 10 pS, 220 ± 8 pS, 152 ± 8 pS and 13 ± 3 pS in a
gradient of 450/150 mM KCl, pH 7.0. A multiconductance potassium channel with a conductivity of 110 ± 8 pS and 31 ± 4 pS was
also found. With the exception of the 13 pS conductance channel, all are activated by depolarizing voltages. One type of chloride
channel was also found. It has a unitary conductance of about 250 pS in a gradient of 500/150 mM KCl, pH 7.0. 相似文献
119.
In this study, we investigated the effects of arachidonic acid, a PLA2-produced lipid metabolite, on the lysosomal permeability, osmotic sensitivity and stability. Through the measurements of lysosomal β-hexosaminidase free activity, membrane potential, intralysosomal pH, and lysosomal latency loss in hypotonic sucrose medium, we established that arachidonic acid could increase the lysosomal permeability to both potassium ions and protons, and enhance the lysosomal osmotic sensitivity. As a result, the fatty-acid-promoted entry of potassium ions into the lysosomes via K+/H+ exchange, which could produce osmotic imbalance across their membranes and osmotically destabilize the lysosomes. In addition, the enhancement of lysosomal osmotic sensitivity caused the lysosomes to become more liable to destabilization in osmotic shock. The results suggest that arachidonic acid may play a role in the lysosomal destabilization. 相似文献
120.
Potassium channels are tetrameric membrane-spanning proteins that provide a selective pore for the conduction of K(+) across the cell membranes. One of the main physiological functions of potassium channels is efficient and very selective transport of K(+) ions through the membrane to the cell. Classical views of ion selectivity are summarized within a historical perspective, and contrasted with the molecular dynamics (MD) simulations free energy perturbation (FEP) performed on the basis of the crystallographic structure of the KcsA phospholipid membrane. The results show that the KcsA channel does not select for K(+) ions by providing a binding site of an appropriate (fixed) cavity size. Rather, selectivity for K(+) arises directly from the intrinsic local physical properties of the ligands coordinating the cation in the binding site, and is a robust feature of a pore symmetrically lined by backbone carbonyl groups. Further analysis reveals that it is the interplay between the attractive ion-ligand (favoring smaller cation) and repulsive ligand-ligand interactions (favoring larger cations) that is the basic element governing Na(+)/K(+) selectivity in flexible protein binding sites. Because the number and the type of ligands coordinating an ion directly modulate such local interactions, this provides a potent molecular mechanism to achieve and maintain a high selectivity in protein binding sites despite a significant conformational flexibility. 相似文献