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71.
72.
Using the patch clamp technique, we have characterized a small conductance, calcium-activated potassium (SK) channel in the C6 glioma cell line. Elevation of cytosolic Ca2+ concentration ([Ca2+]
i
) by applications of serotonin or ionomycin induced bursts of channel openings recorded in the cell-attached configuration. These channels underlie the serotonin-induced, [Ca2+]
i
-activated whole-cell K+ conductance described previously. [Ca2+]
i
directly activated SK channels in inside-out patches with a biphasic concentration dependence. Submicromolar [Ca2+]
i
induced bursts of channel openings with a unitary conductance of about 25 pS, similar to that of the serotonin-induced channels. Supramicromolar [Ca2+]
i
caused prolonged openings with a unitary conductance of about 35 pS, resulting in a pronounced increase of the average current in patches exposed to [Ca2+]
i
above 100 m. The two modes of opening reflect the activity of the same SK channel. The channel conductance depended on external K+ concentration with K
Dof 5 m. The channel was slightly permeable to cations other than K+, with a permeability ratio for K+Ca2+Na+ of 10.0400.030, respectively. ATP was required to maintain channel activity in outside-out patches but was not essential in inside-out patches. The modulation of SK channels in C6 cells by components in their microenvironment may be related to the role of glial cells in controlling the extracellular milieu in the CNS.The authors are grateful to Dr. M. Segal for continuous support, stimulating discussions and criticism throughout the course of this work, to Dr. I. Steinberg for helpful suggestions and to Dr. H. Jarosch, for helping with the Fortran application. N.M.'s research was supported in part by BARD, the U.S.-Israel Binational Agricultural Research and Development Fund, grant no. IS-1670-89RC. 相似文献
73.
L. H. Clapp A. M. Gurney N. B. Standen P. D. Langton 《The Journal of membrane biology》1994,140(3):205-213
Tension and patch clamp recording techniques were used to investigate the relaxation of rabbit pulmonary artery and the properties of the K+ current activated by levcromakalim in isolated myocytes. Under whole-cell voltage clamp, holding at –60 mV in symmetrical 139 mm K+, levcromakalim (10 m) induced a noisy inward current of –116 ± 19 pA (n = 13) which developed over 1 to 2 min. This current could be blocked by either glibenclamide (10 m) or phencyclidine (5–50 M) and was unaffected when extracellular Ca2+ was removed. Both these drugs inhibited the levcromakalim-induced relaxation of muscle strips precontracted with 20 mm [K+]
o
. Application of voltage ramps in symmetrical 139 mm K+ confirmed that the levcromakalim-induced current was carried by K+ ions and was weakly voltage dependent over the potential range from –100 to +40 mV.The unitary current amplitude and density of the channels underlying the levcromakalim-activated whole-cell K+ current was estimated from the noise in the current record. We estimate that levcromakalim caused activation of around 300 channels per cell, with a single channel current of 1.1 pA, corresponding to a slope conductance of about 19 pS. Furthermore, cells dialyzed with an ATP-free pipette solution developed a large noisy inward current at –60 mV, which could subsequently be blocked by flash photolysis of caged ATP. Analysis of the noise associated with this current indicated that the single channel amplitude underlying the ATP-blocked current was 1.4 pA, a value similar to that estimated for the levcromakalim-induced current. We conclude that the conductance of this ATP-sensitive channel is likely to be small under physiological conditions and that it is present at low density.We thank SmithKline & Beecham for the gift of levcromakalim, ICI Pharmaceuticals for the gift of charybdotoxin and Prof. D. Colquhoun for the noise analysis programs. We also thank Mr. R. Davey for technical assistance with tension experiments. This work was supported by the British Heart Foundation and the Wellcome Trust. L.H.C. is a Wellcome Research Fellow and P.L. is an intermediate fellow of the BHF. 相似文献
74.
Elementary Na+ currents were recorded at 19°C in inside-out patches from cultured neonatal rat cardiocytes. In analyzing the sensitivity of chemically modified Na+ channels to several class 1 antiarrhythmic drugs, the hypothesis was tested that removal of Na+ inactivation may be accompanied by a distinct responsiveness to these drugs, open channel blockade.Iodate-modified and trypsin-modified cardiac Na+ channels are noninactivating but strikingly differ from each other by their open state kinetics, a O1–O2 reaction (open(1) 1.4±0.3 msec; open(2) 5.4±1.1 msec; at –40 mV) in the former and a single open state (open 3.0±0.5 msec; at –40 mV) in the latter. Lidocaine (150 mol/liter) like propafenone (10 mol/liter), diprafenone (10 mol/liter) and quinidine (20 mol/liter) in cytoplasmic concentrations effective to depress NP
o
significantly can interact with both types of noninactivating Na+ channels to reduce the dwell time in the conducting configuration. lodate-modified Na+ channels became drug sensitive during the O2 state. At –40 mV, for example, lidocaine reduced open(2) to 62±5% of the control without detectable changes in open(1). No evidence could be obtained that these inhibitory molecules would flicker-block the open Na+ pore. Drug-induced shortening of the open state, thus, is indicative for a distinct mode of drug action, namely interference with the gating process. Lidocaine proved less effective to reduce open(2) when compared with the action of diprafenone. Both drugs apparently interacted with individual association rate constants, alidocaine was 0.64×106 mol–1 sec–1 and adiprafenone 13.6×106 mol–1 sec–1. Trypsin-modified Na+ channels also appear capable of discriminating among these antiarrhythmics, the ratio adiprafenone/alidocaine even exceeded the value in iodate-modified Na+ channels. Obviously, this antiarrhythmic drug interaction with chemically modified Na+ channels is receptor mediated: drug occupation of such a hypothetical hidden receptor that is not available in normal Na+ channels may facilitate the exit from the open state.This work was supported by a grant of the Deutsche Forschungsgemeinschaft (Ko 778/2-4), Bonn. 相似文献
75.
Shiaw-Der Yang Jau-Song Yu Shine-Gwo Shiah Jun-Jae Huang 《Journal of neurochemistry》1994,63(4):1416-1425
In this work, we tested the effect of ion channel blockers and of phorbol ester treatments on [3 H]dopamine ([3 H]DA) release and neurotensin (NT)-induced facilitation of [3 H]DA release from cultures of rat fetal mesencephalic cells. The potassium channel blockers tetraethylammonium and 4-aminopyridine increased basal [3 H]DA release and decreased K+ -evoked [3 H]DA release, whereas apamin was without effect. K+ -evoked [3 H]DA release was decreased by ω-conotoxin and nifedipine, totally suppressed by cadmium, and unaffected by amiloride. These results show the differential sensitivity of [3 H]DA release to blockade of various ion channels and suggest the involvement of N-type, L-type, and non-L-non-N-type, but not T-type, voltage-sensitive calcium channels in K+ -evoked release. Phorbol 12-myristate 13-acetate increased both spontaneous and K+ -evoked [3 H]DA release, suggesting a modulatory action of protein kinase C on DA release in this system. Unexpectedly, however, the effects of the phorbol ester were not counteracted by the protein kinase C inhibitors H7, staurosporine, or polymyxin B. NT-induced facilitation of K+ -evoked [3 H]DA release was insensitive to most of the ion channel blockers, except cadmium (64% decrease in NT effect), suggesting that the corresponding potassium' and calcium channels were not involved in the effect of NT on [3 H]DA release in this system. The NT effect was totally suppressed by phorbol ester treatments, indicating a possible desensitization of the corresponding transduction mechanisms after protein kinase C activation. 相似文献
76.
Abstract: The effects of prostaglandin E2 (PGE2) on 86Rb efflux from rat brain synaptosomes were studied to explore its role in nerve ending potassium (K+) channel modulation. A selective dose-dependent inhibition of the calcium-activated charybdotoxin-sensitive component of efflux was found upon application of PGE2. No significant effect was seen on basal and voltage-dependent components over the concentration range of 10–8 to 10–5M. The protein kinase C (PKC) inhibitors H-7 (10 μM) and staurosporine (100 nM), as well as prolonged preincubation (90 min) with 40-phorbol 12, 13-dibutyrate, which has been reported to down-regulate PKC, abolished the PGE2-in- duced inhibition, whereas HA1004 (10 μM) and Rp-3′,5’cyclic phosphorothioate (100 nM), which are relatively more selective for protein kinase A than PKC, did not. 4β-Phorbol 12, 13-dibutyrate (100 nM), an activator of PKC, produced a similar inhibition of the Ca2+-dependent component of 86Rb efflux but also had no effect on the basal and voltage-dependent components. These data suggest that PGE2 can inhibit rat brain nerve ending calcium-activated 86Rb efflux, and this inhibition may involve PKC activation. 相似文献
77.
Patrick Doherty Josie Furness Emma J. Williams Frank S. Walsh 《Journal of neurochemistry》1994,62(6):2124-2131
Abstract: Activation of tyrosine kinases is established as an important mechanism for controlling growth cone motility and neurite outgrowth. We have tested the effects of a range of tyrosine kinase inhibitors on neurite outgrowth from postnatal day 4 cerebellar granule cells cultured over confluent monolayers of 3T3 fibroblasts. The only agent that had any effect was herbimycin A, which stimulated neurite outgrowth. The response is shown to be attributable to a direct effect of this tyrosine kinase inhibitor on neurones. The neurite outgrowth response to herbimycin A was inhibited by two other tyrosine kinase inhibitors, which on their own did not affect neurite outgrowth. The data suggest that the response to herbimycin A reflects either a direct or indirect activation of one or more protein tyrosine kinases. Independent signalling events downstream from tyrosine kinase activation underlying the neurite outgrowth response to herbimycin A include increased activity of protein kinase C and calcium influx into neurones through both N-and L-type calcium channels. 相似文献
78.
Ion channels are found in most plant membranes. They catalyse the rapid passive uniport of particular ions with varying selectivity. Planar lipid-bilayer (PLB) techniques have been developed to study the electrical activities of single ion channels in well-defined lipid and aqueous environments. They greatly facilitate both the biophysical and biochemical characterisation of ion channels and complement both conventional impaling electrode and membrane-patch voltage-clamping (patch-clamping) electrophysiological techniques applied in vivo. Bilayers can be formed across the end of patch-clamp pipettes or across apertures in specifically designed chambers. Ion channels in native membranes and purified, genetically altered or synthetic ion channels, proteins and peptides can all be studied in PLBs. The main applications of PLBs are (1) to study ion channels in membranes inaccessible to patch-clamp electrodes, (2) to provide a functional assay system during channel-protein purification and (3) to investigate the relationship between the molecular structure of ion channels and their conductance properties. In the present article we describe the techniques available for reconstitution and analysis of ion channels in PLBs and discuss how the PLB technique has been, and may be, useful to the study of plant ion channels. 相似文献
79.
M. Goldermann W. Hanke W. R. Schlue 《Journal of comparative physiology. A, Neuroethology, sensory, neural, and behavioral physiology》1994,174(2):231-237
Two types of potassium channels of identified (p-) neurones of the leech (Hirudo medicinalis) were investigated by using the patch-clamp technique. The openstate probability of these channels in cell-attached patches can be reduced by addition of 5-hydroxytryptamine to the bath solution. After excising the patches the application of alkaline phosphatase to the cytosolic face of the patch increases the open probability. The 5-HT1A-receptor agonist buspirone mimics the effect of 5-HT. Our experiments show that the effect of 5-HT might be due to a channel phosphorylation via a 5-HT1A-receptor subtype. 相似文献
80.
W. -M. Weber B. Dannenmaier W. Clauss 《Journal of comparative physiology. B, Biochemical, systemic, and environmental physiology》1993,163(2):153-159
The dorsal skin of the leech Hirudo medicinalis was used for electrophysiological measurements performed in Ussing chambers. The leech skin is a tight epithelium (transepithelial resistance = 10.5±0.5 k· cm-2) with an initial short-circuit current of 29.0±2.9 A·cm-2. Removal of Na+ from the apical bath medium reduced short-circuit current about 55%. Ouabain (50mol·l-1) added to the basolateral solution, depressed the short-circuit current completely. The Na+ current saturated at a concentration of 90 mmol Na+·l-1 in the apical solution (K
M=11.2±1.8 mmol·l-1). Amiloride (100 mol·l-1) on the apical side inhibited ca. 40% of the Na+ current and indicated the presence of Na+ channels. The dependence of Na+ current on the amiloride concentration followed Michaclis-Menten kinetics (K
i=2.9±0.4 mol·l-1). The amiloride analogue benzamil had a higher affinity to the Na+ channel (K
i=0.7±0.2 mol·l-1). Thus, Na+ channels in leech integument are less sensitive to amiloride than channels known from vertebrate epithelia. With 20 mmol Na+·l-1 in the mucosal solution the tissue showed an optimum amiloride-inhibitable current, and the amiloride-sensitive current under this condition was 86.8±2.3% of total short-circuit current. Higher Na+ concentrations lead to a decrease in amiloride-blockade short-circuit current. Sitmulation of the tissue with cyclic adenosine monophosphate (100 mol·l-1) and isobutylmethylxanthine (1 mmol·l-1) nearly doubled short-circuit current and increased amiloride-sensitive Na+ currents by 50%. By current fluctuation analysis we estimated single Na+ channel current (2.7±0.9 pA) and Na+ channel density (3.6±0.6 channels·m-2) under control conditions. After cyclic adenosine monophosphate stimulation Na+ channel density increased to 5.4±1.1 channels·m-2, whereas single Na+ channel current showed no significant change (1.9±0.2 pA). These data present a detailed investigation of an invertebrate epithelial Na+ channel, and show the similarities and differences to vertebrate Na+ channels. Whereas the channel properties are different from the classical vertebrate Na+ channel, the regulation by cyclic adenosine monophosphate seems similar. Stimulation of Na+ uptake by cyclic adenosine monophosphate is mediated by an increasing number of Na+ channels.Abbreviations
slope of the background noise component
- ADH
antidiuretic hormone
- cAMP
cyclic adenosine monophosphate
-
f
frequency
-
f
c
coner frequency of the Lorentzian noise component
- Hepes
N-hydroxyethylpiperazine-N-ethanesulphonic acid
- BMX
isobutyl-methylxanthine
-
i
Na
single Na+ channel current
-
I
Na
max, maximal inhibitable Na+ current
-
I
SC
short circuit current
-
K
i
half maximal blocker concentration
-
K
M
Michaelis constandard error of the mean
-
S
(f)
power density of the Lorentzian noise component
-
S
0
plateau value of the Lorentzian noise component
- TMA
tetramethylammonium
- Trizma
TRIS-hydroxymethyl-amino-methane
-
V
max
maximal reaction velocity
-
V
T
transepithelial potential
-
K
half maximal blocker concentration 相似文献