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1.
A modified Parsegian formula for calculating the image force in a water pore, which takes into account nonlocal electrostatic effects, has been applied to analysis of changes in the permeability of K+ channels. It is shown that the channel permeability increases ~3000 times as the width of the pore increases from 4 to 10 Å when the energy is calculated by the modified formula, but only 16 times if the classical Parsegian formula is used. We conclude that the image force in the K+ channel water pore plays an important part in the change of channel permeability, and the sensitivity of channel permeability to the pore width is greatly enhanced by nonlocal electrostatic effects. 相似文献
2.
Site-specific mutations in a minimal voltage-dependent K+ channel alter ion selectivity and open-channel block 总被引:6,自引:0,他引:6
MinK is a small membrane protein of 130 amino acids with a single potential membrane-spanning alpha-helical domain. Its expression in Xenopus oocytes induces voltage-dependent, K(+)-selective channels. Using site-directed mutagenesis of a synthetic gene, we have identified residues in the hydrophobic region of minK that influence both ion selectivity and open-channel block. Single amino acid changes increase the channel's relative permeability for NH4+ and Cs+ without affecting its ability to exclude Na+ and Li+. Blockade by two common K+ channel pore blockers, tetraethylammonium and Cs+, was also modified. These results suggest that an ion selectivity region and binding sites for the pore blockers within the conduction pathway have been modified. We conclude that the gene encoding minK is a structural gene for a K+ channel protein. 相似文献
3.
The ability of an ion channel to open in response to a defined stimulus is central to its function. In ligand-gated channels, pore opening is conferred through transduction of a conformational change in a gating domain to the helices of the pore. Here, we present the construction of a designed cyclic nucleotide-gated (CNG) channel, named KcsA-CNG, by addition of a prokaryotic cyclic nucleotide-binding domain to a KcsA-derived K+ channel. This channel is functional in lipid bilayers at physiological pH and has the combined properties of both of its parent-derived components. It conducts K+ and is blocked by the K+ channel inhibitors Na+ and agitoxin-2. Channel open times are increased by about two orders of magnitude compared to wild-type KcsA. The average number of open channels increases by approximately 50% upon addition of cAMP. Although the absolute open probabilities are somewhat variable from one channel to the next, the property of cyclic nucleotide sensitivity is very reproducible. An apparent Kd value of approximately 90 nM was estimated. The successful construction of a cyclic nucleotide-gated KcsA K+ channel suggests that it should be possible to produce channels that will respond to novel ligands. 相似文献
4.
Previous studies have reported that the KcsA potassium channel has an osmotic permeability coefficient of 4.8 x 10(-12) cm3/s, giving it a significantly higher osmotic permeability coefficient than that of some membrane channels specialized in water transport. This high osmotic permeability is proposed to occur when the channel is depleted of potassium ions, the presence of which slow down the water permeation process. The atomic structure of the potassium-depleted KcsA channel and the mechanisms of water permeation have not been well characterized so far. Here, all-atom molecular dynamics simulations, in conjunction with an umbrella sampling strategy and a nonequilibrium approach to simulate pressure gradients are employed to illustrate the permeation of water in the absence of ions through the KcsA K+ channel. Equilibrium molecular dynamics simulations (95 ns combined total length) identified a possible structure of the potassium-depleted KcsA channel, and umbrella sampling calculations (160 ns combined total length) revealed that this structure is not permeable by water molecules moving along the channel axis. The simulation of a pressure gradient across the channel (30 ns combined total length) identified an alternative permeation pathway with a computed osmotic permeability of approximately (2.7 +/- 0.9) x 10(-13) cm3/s. Water fluxes along this pathway did not proceed through collective water motions or transitions to vapor state. All of the major results of this study were robust against variations in a wide set of simulation parameters (force field, water model, membrane model, and channel conformation). 相似文献
5.
Selectivity and gating of the type L potassium channel in mouse lymphocytes 总被引:8,自引:4,他引:4
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Type l voltage-gated K+ channels in murine lymphocytes were studied under voltage clamp in cell-attached patches and in the whole-cell configuration. The kinetics of activation of whole-cell currents during depolarizing pulses could be fit by a single exponential after an initial delay. Deactivation upon repolarization of both macroscopic and microscopic currents was mono-exponential, except in Rb-Ringer or Cs-Ringer solution in which tail currents often displayed "hooks," wherein the current first increased or remained constant before decaying. In some cells type l currents were contaminated by a small component due to type n K+ channels, which deactivate approximately 10 times slower than type l channels. Both macroscopic and single channel currents could be dissected either kinetically or pharmacologically into these two K+ channel types. The ionic selectivity and conductance of type l channels were studied by varying the internal and external permeant ion. With 160 mM K+ in the cell, the relative permeability calculated from the reversal potential with the Goldman-Hodgkin-Katz equation was K+ (identical to 1.0) greater than Rb+ (0.76) greater than NH4+ = Cs+ (0.12) much greater than Na+ (less than 0.004). Measured 30 mV negative to the reversal potential, the relative conductance sequence was quite different: NH4+ (1.5) greater than K+ (identical to 1.0) greater than Rb+ (0.5) greater than Cs+ (0.06) much greater than Na+, Li+, TMA+ (unmeasurable). Single channel current rectification resembled that of the whole-cell instantaneous I-V relation. Anomalous mole-fraction dependence of the relative permeability PNH4/PK was observed in NH4(+)-K+ mixtures, indicating that the type l K+ channel is a multi-ion pore. Compared with other K+ channels, lymphocyte type l K+ channels are most similar to "g12" channels in myelinated nerve. 相似文献
6.
Calcium channel selectivity for divalent and monovalent cations. Voltage and concentration dependence of single channel current in ventricular heart cells 总被引:53,自引:22,他引:31
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Single channel and whole cell recordings were used to study ion permeation through Ca channels in isolated ventricular heart cells of guinea pigs. We evaluated the permeability to various divalent and monovalent cations in two ways, by measuring either unitary current amplitude or reversal potential (Erev). According to whole cell measurements of Erev, the relative permeability sequence is Ca2+ greater than Sr2+ greater than Ba2+ for divalent ions; Mg2+ is not measurably permeant. Monovalent ions follow the sequence Li+ greater than Na+ greater than K+ greater than Cs+, and are much less permeant than the divalents. These whole cell measurements were supported by single channel recordings, which showed clear outward currents through single Ca channels at strong depolarizations, similar values of Erev, and similar inflections in the current-voltage relation near Erev. Information from Erev measurements stands in contrast to estimates of open channel flux or single channel conductance, which give the sequence Na+ (85 pS) greater than Li+ (45 pS) greater than Ba2+ (20 pS) greater than Ca2+ (9 pS) near 0 mV with 110-150 mM charge carrier. Thus, ions with a higher permeability, judged by Erev, have lower ion transfer rates. In another comparison, whole cell Na currents through Ca channels are halved by less than 2 microM [Ca]o, but greater than 10 mM [Ca]o is required to produce half-maximal unitary Ca current. All of these observations seem consistent with a recent hypothesis for the mechanism of Ca channel permeation, which proposes that: ions pass through the pore in single file, interacting with multiple binding sites along the way; selectivity is largely determined by ion affinity to the binding sites rather than by exclusion by a selectivity filter; occupancy by only one Ca ion is sufficient to block the pore's high conductance for monovalent ions like Na+; rapid permeation by Ca ions depends upon double occupancy, which only becomes significant at millimolar [Ca]o, because of electrostatic repulsion or some other interaction between ions; and once double occupancy occurs, the ion-ion interaction helps promote a quick exit of Ca ions from the pore into the cell. 相似文献
7.
Small-conductance Ca2+-activated potassium channels (SK(Ca) channels) are heteromeric complexes of pore-forming main subunits and constitutively bound calmodulin. SK(Ca) channels in neuronal cells are activated by intracellular Ca2+ that increases during action potentials, and their ionic currents have been considered to underlie neuronal afterhyperpolarization. However, the ion selectivity of neuronal SK(Ca) channels has not been rigorously investigated. In this study, we determined the monovalent cation selectivity of a cloned rat SK(Ca) channel, rSK2, using heterologous expression and electrophysiological measurements. When extracellular K+ was replaced isotonically with Na+, ionic currents through rSK2 reversed at significantly more depolarized membrane potentials than the value expected for a Nernstian relationship for K+. We then determined the relative permeability of rSK2 for monovalent cations and compared them with those of the intermediate- and large-conductance Ca2+-activated K+ channels, IK(Ca) and BK(Ca) channels. The relative permeability of the rSK2 channel was determined as K+(1.0)>Rb+(0.80)>NH(4)+(0.19) approximately Cs+(0.19)>Li+(0.14)>Na+(0.12), indicating substantial permeability of small ions through the channel. Although a mutation near the selectivity filter mimicking other K+-selective channels influenced the size-selectivity for permeant ions, Na+ permeability of rSK2 channels was still retained. Since the reversal potential of endogenous SK(Ca) current is determined by Na+ permeability in a physiological ionic environment, the ion selectivity of native SK(Ca) channels should be reinvestigated and their in vivo roles may need to be restated. 相似文献
8.
V Z Lunevski? O M Zherelova A A Aleksandrov M G Vinokurov G N Berestovski? 《Biofizika》1980,25(4):685-691
The present work was intended to further investigate the selective filter of calcium channel on both a cell membrane and reconstructed channels. For the studies on cell membranes, an inhibitor of chloride channels was chosen (ethacrynic acid) to pass currents only through the calcium channels. On both the cells and reconstructed channels, permeability of ions of different crystal radii and valencies was investigated. The obtained results suggest that the channel represents a wide water pore with a diameter larger than 8 A into which ions go together with the nearest water shell. The values of the maximal currents are given by electrostatic interaction of the ions with the anion center of the channel. A phenomenological two-barrier model of the channel is given which describes the movement of all the ions studied. 相似文献
9.
Hazama A Kozono D Guggino WB Agre P Yasui M 《The Journal of biological chemistry》2002,277(32):29224-29230
Aquaporin-6 (AQP6) has recently been identified as an intracellular vesicle water channel with anion permeability that is activated by low pH or HgCl2. Here we present direct evidence of AQP6 channel gating using patch clamp techniques. Cell-attached patch recordings of AQP6 expressed in Xenopus laevis oocytes indicated that AQP6 is a gated channel with intermediate conductance (49 picosiemens in 100 mm NaCl) induced by 10 microm HgCl2. Current-voltage relationships were linear, and open probability was fairly constant at any given voltage, indicating that Hg2+-induced AQP6 conductance is voltage-independent. The excised outside-out patch recording revealed rapid activation of AQP6 channels immediately after application of 10 microm HgCl2. Reduction of both Na+ and Cl- concentrations from 100 to 30 mm did not shift the reversal potential of the Hg2+-induced AQP6 current, suggesting that Na+ is as permeable as Cl-. The Na+ permeability of Hg2+-induced AQP6 current was further demonstrated by 22Na+ influx measurements. Site-directed mutagenesis identified Cys-155 and Cys-190 residues as the sites of Hg2+ activation both for water permeability and ion conductance. The Hill coefficient from the concentration-response curve for Hg2+-induced conductance was 1.1 +/- 0.3. These data provide the first evidence of AQP6 channel gating at a single-channel level and suggest that each monomer contains the pore region for ions based on the number of Hg2+-binding sites and the kinetics of Hg2+-activation of the channel. 相似文献
10.
Modeling of the pore domain of the GLUR1 channel: homology with K+ channel and binding of channel blockers
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Molecular models of the M2 segments of the GluR1 channel have been elaborated using a molecular mechanics approach. The models are based on the homology between pore-lining segments of AMPA receptor channels and the KcsA K+ channel and on cyclic H bonds at the Q/R site of the AMPA receptor channel. The N-terminal region of an M2 segment of the channel is assumed, like that of the K+ channel, to adopt a helical conformation. Due to a deletion, the C-terminal end of the M2 segment of the AMPA receptor is more stretched than that of the K+ channel. As a result, only a single oxygen ring may be exposed to the AMPA receptor channel pore. Data on the block of AMPA receptor channels by dicationic adamantane derivatives have been used to select the most relevant model. The model with the oxygen of a Gly residue (position +2 from the Q/R site) exposed to the pore best fits the experimental data. This model also fits experimental data for another class of AMPA receptor antagonists, the polyamine amides. According to the model, the side-chains of the C-terminal residues are involved in intra-receptor interactions that stabilize the structure of the channel rather than in interactions with ions in the pore. 相似文献
11.
Potassium channels are exquisitely selective, allowing K+ to pass across cell membranes while blocking other ion types. Here we demonstrate that the number of carbonyl oxygen atoms that surround permeating ions is the most important factor in determining ion selectivity rather than the size of the pore or the strength of the coordinating dipoles. Although the electrostatic properties of the coordinating ligands can lead to Na+ or K+ selectivity at some values of the dipole moment, no significant selectivity arises at the specific value of the dipole moment for carbonyl groups found in potassium channels when the ligands have complete freedom. Rather, we show that the main contribution to selectivity arises from slight constraints on the conformational freedom of the channel protein that limit the number of carbonyl oxygen atoms to a value better suited to K+ than Na+, despite the pore being flexible. This mechanism provides an example of a general framework for explaining ion discrimination in a range of natural and synthetic macromolecules in which selectivity is controlled by the number of coordinating ligands in addition to their dipole moment. 相似文献
12.
Roles of K149, G352, and H401 in the channel functions of ClC-0: testing the predictions from theoretical calculations
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The ClC family of Cl(-) channels and transporters comprises membrane proteins ubiquitously present in species ranging from prokaryotes to mammals. The recently solved structures of the bacterial ClC proteins have provided a good model to guide the functional experiments for the eukaryotic Cl(-) channels. Theoretical calculations based on the bacterial ClC structures have identified several residues critical for the Cl(-) binding energy in the Cl(-) transport pathway. It was speculated that the corresponding residues in eukaryotic Cl(-) channels might play similar roles for the channel functions. In this study, we made a series of mutations in three such residues in eukaryotic ClC Cl(-) channels (K149, G352, and H401 in ClC-0) and studied the functional consequences on the channel properties. A cysteine modification approach was also employed to evaluate the electrostatic effects of the charge placed at these three positions. The experimental results revealed that among the three residues tested, K149 plays the most important role in controlling both the gating and the permeation functions of ClC-0. On the other hand, mutations of H401 alter the channel conductance but not the gating properties, while mutations of G352 result in very little functional consequence. The mutation of K149 into a neutral residue leucine (K149L) shifts the activation curve and leads to flickery channel openings. The anion permeability ratios derived from bi-ionic experiments are also significantly altered in that the selectivity of Cl(-) over other anions is decreased. Furthermore, removing the positive charge at this position reduces and increases, respectively, the accessibility of the negatively and positively charged methane thiosulfonate reagents to the pore. The control of the accessibility to charged MTS reagents and the regulation of the anion permeation support the idea that K149 exerts an electrostatic effect on the channel function, confirming the prediction from computational studies. 相似文献
13.
Zhen XG Xie C Fitzmaurice A Schoonover CE Orenstein ET Yang J 《The Journal of general physiology》2005,126(3):193-204
The inner pore of voltage-gated Ca2+ channels (VGCCs) is functionally important, but little is known about the architecture of this region. In K+ channels, this part of the pore is formed by the S6/M2 transmembrane segments from four symmetrically arranged subunits. The Ca2+ channel pore, however, is formed by four asymmetric domains of the same (alpha1) subunit. Here we investigated the architecture of the inner pore of P/Q-type Ca2+ channels using the substituted-cysteine accessibility method. Many positions in the S6 segments of all four repeats of the alpha1 subunit (Ca(v)2.1) were modified by internal methanethiosulfonate ethyltrimethylammonium (MTSET). However, the pattern of modification does not fit any known sequence alignment with K+ channels. In IIS6, five consecutive positions showed clear modification, suggesting a likely aqueous crevice and a loose packing between S6 and S5 segments, a notion further supported by the observation that some S5 positions were also accessible to internal MTSET. These results indicate that the inner pore of VGCCs is indeed formed by the S6 segments but is different from that of K+ channels. Interestingly some residues in IIIS6 and IVS6 whose mutations in L-type Ca2+ channels affect the binding of dihydropyridines and phenylalkylamines and are thought to face the pore appeared not to react with internal MTSET. Probing with qBBr, a rigid thiol-reactive agent with a dimension of 12 angstroms x 10 angstroms x 6 angstroms suggests that the inner pore can open to >10 angstroms. This work provides an impetus for future studies on ion permeation, gating, and drug binding of VGCCs. 相似文献
14.
The results of further investigations on a single potential dependent K+ channel are described. It was shown that ionic selectivity of the channel for monovalent ions is too high: Li+, Na+, and Cs+ are practically impermeant ions. Permeability of the channel for Rb+ is approximately 10 times less, and for Tl+ it is 2 times more than permeability for K+. Besides, it was found that open K+ channel has 16 multiple conductance levels. 相似文献
15.
A microscopic model of an amphotericin B channel is proposed. The structure of the pores is generated using the atomic coordinates of the molecule in the structure determined experimentally by X-ray diffraction. The net charges of the atoms are determined by Mulliken analysis. With these charges the electrostatic energy profiles are calculated for a monovalent ion passing through the channels formed by different number of antibiotic molecules having different radii. The water inside the channel was considered through a continuum medium using the dielectric constant of the bulk, and the membrane contribution was included using the virtual images of the pore in a dielectric slab of epsilon = 3. The model satisfactorily explains the permeability and selectivity characteristics as well as other observations yet unexplained. The electrostatic profiles obtained reinforce the hypothesis of the existence of channels formed by a variable number of units. 相似文献
16.
Conduction through the inward rectifier potassium channel, Kir2.1, is increased by negatively charged extracellular residues
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D'Avanzo N Cho HC Tolokh I Pekhletski R Tolokh I Gray C Goldman S Backx PH 《The Journal of general physiology》2005,125(5):493-503
Ion channel conductance can be influenced by electrostatic effects originating from fixed "surface" charges that are remote from the selectivity filter. To explore whether surface charges contribute to the conductance properties of Kir2.1 channels, unitary conductance was measured in cell-attached recordings of Chinese hamster ovary (CHO) cells transfected with Kir2.1 channels over a range of K+ activities (4.6-293.5 mM) using single-channel measurements as well as nonstationary fluctuation analysis for low K+ activities. K+ ion concentrations were shown to equilibrate across the cell membrane in our studies using the voltage-sensitive dye DiBAC4(5). The dependence of gamma on the K+ activity (a(K)) was fit well by a modified Langmuir binding isotherm, with a nonzero intercept as a(K) approaches 0 mM, suggesting electrostatic surface charge effects. Following the addition of 100 mM N-methyl-D-glucamine (NMG+), a nonpermeant, nonblocking cation or following pretreatment with 50 mM trimethyloxonium (TMO), a carboxylic acid esterifying agent, the gamma-a(K) relationship did not show nonzero intercepts, suggesting the presence of surface charges formed by glutamate or aspartate residues. Consistent with surface charges in Kir2.1 channels, the rates of current decay induced by Ba2+ block were slowed with the addition of NMG or TMO. Using a molecular model of Kir2.1 channels, three candidate negatively charged residues were identified near the extracellular mouth of the pore and mutated to cysteine (E125C, D152C, and E153C). E153C channels, but not E125C or D152C channels, showed hyperbolic gamma-a(K) relationships going through the origin. Moreover, the addition of MTSES to restore the negative charges in E53C channels reestablished wild-type conductance properties. Our results demonstrate that E153 contributes to the conductance properties of Kir2.1 channels by acting as a surface charge. 相似文献
17.
To gain an insight into the molecular basis of ion permeation mechanism through the nicotinic acetylcholine receptor (AChR) channel, we have determined permeability ratios of organic cations relative to Na+ of specifically mutated Torpedo californica AChR channels expressed in Xenopus oocytes. The mutations involved mainly the side chains of the amino acid residues in the intermediate ring, where mutations have been found to exert strong effects on single-channel conductance and ion selectivity among alkali metal cations. The results obtained reveal that both the size and the net charge of the side chains of the intermediate ring are involved in determining the permeability, and provide experimental evidence that the pore size at the intermediate ring is a critical determinant of permeability. Our findings further suggest that changes in net charge exert effects on permeability by affecting the pore size of the channel. 相似文献
18.
Verdier L Al-Sabi A Rivier JE Olivera BM Terlau H Carlomagno T 《The Journal of biological chemistry》2005,280(22):21246-21255
KappaM-conotoxin RIIIK blocks TSha1 K+ channels from trout with high affinity by interacting with the ion channel pore. As opposed to many other peptides targeting K+ channels, kappaM-RIIIK does not possess a functional dyad. In this study we combine thermodynamic mutant cycle analysis and docking calculations to derive the binding mode of kappaM-conotoxin RIIIK to the TSha1 channel. The final model reveals a novel pharmacophore, where no positively charged side chain occludes the channel pore. Instead the positive-charged residues of the toxin form a basic ring; kappaM-RIIIK is anchored to the K+ channel via electrostatic interactions of this basic ring with the loop and pore helix residues of the channel. The channel amino acid Glu-354 is likely to be a fundamental determinant of the selectivity of kappaM-RIIIK for the TSha1 channel. The Cgamma-OH of Hyp-15 is in contact with the carbonyls of the selectivity filter, disturbing the charge distribution pattern necessary for the coordination of K+ ions. This novel, experimentally based pharmacophore model proves the existence of diverse binding modes of peptidic toxins to K+ channels and underlines the role of intermolecular electrostatic interactions involving channel loop side chains in determining the selectivity of toxins for specific K+ channel types. 相似文献
19.
This study is an investigation of the ability of the bacterial channel alpha-hemolysin to facilitate water permeation across biological membranes. alpha-Hemolysin channels were incorporated into rabbit erythrocyte ghosts at varying concentrations, and water permeation was induced by mixing the ghosts with hypertonic sucrose solutions. The resulting volume decrease of the ghosts was followed by time-resolved optical absorption at pH 5, 6, and 7. The average single-channel permeability coefficient of alpha-hemolysin for water ranged between 1.3x10-12 cm/s and 1.5x10-12 cm/s, depending on pH. The slightly increased single-channel permeability coefficient at lower pH-values was attributed to an increase in the effective pore size. The activation energy of water transport through the channel was low (Ea=5.4 kcal/mol), suggesting that the properties of water inside the alpha-hemolysin channel resemble those of bulk water. This conclusion was supported by calculations based on macroscopic hydrodynamic laws of laminar water flow. Using the known three-dimensional structure of the channel, the calculations accurately predicted the rate of water flow through the channel. The latter finding also indicated that water permeation data can provide a good estimate of the pore size for large channels. 相似文献
20.
Lourdel S Paulais M Marvao P Nissant A Teulon J 《The Journal of general physiology》2003,121(4):287-300
The distal-convoluted tubule (DCT) of the kidney absorbs NaCl mainly via an Na+-Cl- cotransporter located at the apical membrane, and Na+, K+ ATPase at the basolateral side. Cl- transport across the basolateral membrane is thought to be conductive, but the corresponding channels have not yet been characterized. In the present study, we investigated Cl- channels on microdissected mouse DCTs using the patch-clamp technique. A channel of approximately 9 pS was found in 50% of cell-attached patches showing anionic selectivity. The NPo in cell-attached patches was not modified when tubules were preincubated in the presence of 10-5 M forskolin, but the channel was inhibited by phorbol ester (10-6 M). In addition, NPo was significantly elevated when the calcium in the pipette was increased from 0 to 5 mM (NPo increased threefold), or pH increased from 6.4 to 8.0 (NPo increased 15-fold). Selectivity experiments conducted on inside-out patches showed that the Na+ to Cl- relative permeability was 0.09, and the anion selectivity sequence Cl(-)--I(-) > Br(-)--NO3(-) > F(-). Intracellular NPPB (10-4 M) and DPC (10-3 M) blocked the channel by 65% and 80%, respectively. The channel was inhibited at acid intracellular pH, but intracellular ATP and PKA had no effect. ClC-K Cl- channels are characterized by their sensitivity to the external calcium and to pH. Since immunohistochemical data indicates that ClC-K2, and perhaps ClC-K1, are present on the DCT basolateral membrane, we suggest that the channel detected in this study may belong to this subfamily of the ClC channel family. 相似文献