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gamma-Aminobutyric acid receptor channels in adrenal chromaffin cells: a patch-clamp study.

We have studied membrane channels activated by gamma-aminobutyric acid (GABA) in adrenal medullary chromaffin cells by using patch-clamp techniques. These channels share many properties with GABA-receptor channels in the central nervous system. They are chloride-selective, blocked by the GABA antagonist bicuculline, and reversibly desensitized at high GABA concentrations. The dose-response curve has a slope of 2 in the Hill plot, indicating a bimolecular binding reaction of GABA to the receptor. Single-channel currents display multiple conductance states as do glycine-activated chloride channels in mouse spinal neurons. Gating properties of GABA-activated channels, as described by a sequential model for agonist-activated channels, are similar to gating properties in central neurons. GABA-induced currents are potentiated by diazepam, indicating that anxiolytic drugs like the benzodiazepines might be involved in the regulation of anxiety states in the peripheral nervous system.

Animals↗

"Optical patch-clamping": single-channel recording by imaging Ca2+ flux through individual muscle acetylcholine receptor channels.

We describe an optical technique using total internal reflection fluorescence (TIRF) microscopy to obtain simultaneous and independent recordings from numerous ion channels via imaging of single-channel Ca2+ flux. Muscle nicotinic acetylcholine (ACh) receptors made up of alphabetagammadelta subunits were expressed in Xenopus oocytes, and single channel Ca2+ fluorescence transients (SCCaFTs) were imaged using a fast (500 fps) electron-multiplied c.c.d. camera with fluo-4 as the indicator. Consistent with their arising through openings of individual nicotinic channels, SCCaFTs were seen only when a nicotinic agonist was present in the bathing solution, were blocked by curare, and increased in frequency as roughly the second power of [ACh]. Their fluorescence amplitudes varied linearly with membrane potential and extrapolated to zero at about +60 mV. The rise and fall times of fluorescence were as fast as 2 ms, providing a kinetic resolution adequate to characterize channel gating kinetics; which showed mean open times of 7.9 and 15.8 ms when activated, respectively, by ACh or suberyldicholine. Simultaneous records were obtained from >400 channels in the imaging field, and we devised a novel "channel chip" representation to depict the resultant large dataset as a single image. The positions of SCCaFTs remained fixed (<100 nm displacement) over tens of seconds, indicating that the nicotinic receptor/channels are anchored in the oocyte membrane; and the spatial distribution of channels appeared random without evidence of clustering. Our results extend single-channel TIRFM imaging to ligand-gated channels that display only partial permeability to Ca2+, and demonstrate an order-of-magnitude improvement in kinetic resolution. We believe that functional single-channel imaging opens a new approach to ion channel study, having particular advantages over patch-clamp recording in that it is massively parallel, and provides high-resolution spatial information that is inaccessible by electrophysiological techniques.

Acetylcholine↗

A patch-clamp study of bovine chromaffin cells and of their sensitivity to acetylcholine.

1. Bovine chromaffin cells were enzymatically isolated and kept in short term tissue culture. Their electrical properties were studied using recent advances of the patch-clamp technique (Hamill, Marty, Neher, Sakmann & Sigworth, 1981). 2. When a patch pipette was sealed tightly to a chromaffin cell ('cell-attached configuration') current wave forms due to intracellular action potentials could be observed. The frequency of the wave forms was altered by changing the pipette potential. When acetylcholine was present in the pipette solution, acetylcholine-induced single channel currents were evident in the patch recording. Action potential wave forms were then often seen to follow acetycholine-induced single channel currents. 3. In the cell-attached configuration, large single channel current events did not resemble square pulses but showed exponential relaxations with time constants of the order of 50 ms. 4. After rupture of the patch of membrane, the pipette--cell seal remained stable ('whole-cell recording', Hamill et al. 1981). Chromaffin cells were found to have a resting potential of -50 to -80 mV, and an input resistance around 5 G omega. The high cell resistance accounts for the relaxing currents evident in the cell-attached configuration. 5. In the best cases, the effective time constant of the voltage clamp in the whole-cell recording mode was 15 microseconds. Exchange of small ions such as Na+ ions between pipette and cell interior solutions was then complete within 15 s. 6. Acetylcholine-induced currents were obtained at various acetylcholine concentrations. Single acetylcholine-induced channels had a slope conductance of 44 pS between -100 and -55 mV, and a mean duration of 27 ms at -80 mV (at room temperature).

Acetylcholine↗

Patch-clamp study of the calcium-dependent chloride current in AtT-20 pituitary cells.

1. Voltage-clamp recordings were made from cultured AtT-20 pituitary cells using the whole-cell patch-clamp technique. Cells were perfused internally with Cs+ to block K+ currents and bathed externally with either 1 microM tetrodotoxin or with tetraethylammonium (TEA) as a Na+ substitute to block voltage-activated Na+ currents. 2. Depolarizing voltage steps from a holding potential of -80 mV to potentials positive to -30 mV evoked two currents: a fast inward current that activated between -30 and +70 mV and a slowly activating current (designated "slow step current") that was inward between -30 and near 0 mV (the Cl- equilibrium potential) and outward positive to about 0 mV. Repolarization to -80 mV revealed a slowly decaying, inward tail current, whose magnitude with respect to step potential closely matched the current-voltage relationship of the voltage-activated Ca2+ current. 3. Activation of the fast inward current, slow step current, and tail current, was prevented by extracellular application of Cd2+ or removal of extracellular Ca2+. Replacement of extracellular Ca2+ with Ba2+ potentiated the fast inward current but blocked the slow step and tail currents. Intracellular perfusion with greater than 1 mM of the Ca2+ chelators ethyleneglycol-bis(beta-aminoethylether)-N,N'-tetraacetic acid (EGTA) or [1,2-bis(2)aminophenoxy]ethane N,N,N',N'-tetraacetic acid (BAPTA) prevented activation of the slow step and tail currents, but not the fast inward current. 4. The reversal potential of the slow inward current was sensitive to changes in the Cl- equilibrium potential but not to substitution of TEA for Na+. The slow step current, but not the fast inward current, was partially blocked by the Cl- channel blocker, 4-acetamido-4'-isothiocyanostilbene-2,2'-disulfonic acid. 5. These data indicate that both the slow inward tail current and the slowly activating, reversible step current were a Ca2+-dependent Cl- current, similar to that described in other neuronal and nonneuronal cell types. The fast inward current was a voltage-activated Ca2+ current, described previously in these and other cells. 6. In the absence of intracellular EGTA, the tail current decayed with complex kinetics, its time course apparently dependent on the magnitude of the voltage-activated Ca2+ current. In the presence of 200 microM intracellular EGTA, the tail current decayed significantly faster and often decayed exponentially.

Animals↗

Intracellular recordings with patch-clamp pipettes from neurons; technical problems in analysis of conductance changes during brief oxygen deprivation of hippocampal slices.

Brief oxygen deprivation causes reversible, rapid and large scale redistribution of ions in hippocampal slice preparations. Intracellular recordings revealed remarkable increases of membrane conductance in neurons restricted for the period of hypoxic spreading depression (SD). Voltage-clamp technique was applied to explore further details of the SD-associated conductance changes. Patch-clamp recording in whole-cell configuration allowed better control of membrane potentials. High resolution current-voltage (I-V) plots were obtained by ramp command technique. Limitations of the techniques and various test protocols are evaluated.

Animals↗

Amiloride-insensitive cation conductance in Xenopus laevis olfactory neurons: a combined patch clamp and calcium imaging analysis.

We used digital calcium imaging with Fura-2 in conjunction with the tight-seal whole-cell patch clamp technique to describe a novel cation conductance in olfactory neurons of the clawed toad Xenopus laevis. Substitution of extracellular Ca2+ and Na+ was used as a tool to change [Ca2+]i. When [Ca2+]i was increased to about 450 nM, a conductance gcat activated that was permeable for cations. Upon gcat activation, an increase in [Ca2+]i occurred in the dendritic knob. Once activated, gcat showed no further dependence upon [Ca2+]i. Icat is shown to be different from the current activated by a mixture of the odorants citralva and amyl acetate. We conclude that there are two different cation conductances in the peripheral compartments of olfactory neurons in X. laevis.

Amiloride↗

Patch-clamp studies of K+ and Cl- channel currents in canine pancreatic acinar cells.

K+ and Cl- channel currents in the plasma membrane of isolated canine pancreatic acinar cells were studied by patch-clamp single-channel and whole-cell current recording techniques. In excised inside-out patches, we found a Ca(2+)-activated (control range 0.01-0.4 microM) and voltage-activated K(+)-selective channel with a unit conductance of approximately 40 pS in symmetrical K(+)-rich solutions. In intact cells, addition of acetylcholine (1 microM) or bombesin tetradecapeptide (0.1 nM) to the bath evoked an increase in frequency of K+ channel opening. In whole-cell recordings on cells dialyzed with K(+)-rich and Ca(2+)-free solution containing 0.5 mM EGTA, the resting potential was about -40 mV. Depolarizing voltage pulses activated outward K+ currents, which were blocked by 10 mM tetraethylammonium, whereas hyperpolarizing pulses evoked smaller inward currents. Acetylcholine or bombesin activated the K+ current and enhanced the inward current, which was reduced by a low Cl- (10 mM) intracellular solution at -90 mV holding potential. These results suggest that both Ca(2+)- and voltage-activated K+ channels and Ca(2+)-activated Cl- channels exist in the plasma membrane of canine pancreatic acinar cells.

Acetylcholine↗

Patch clamp recordings of single ion channel activation by gonadotrophin-releasing hormone in ovine pituitary gonadotrophs.

Gonadotrophs of the ovine pars tuberalis have been studied using the patch clamp technique for recording of single ion channel currents. We report that gonadotrophin-releasing hormone (GnRH) acts on these cells to open an inward-current cation channel which is permeable to Ca2+. When measured in cell-attached patches with 5 mM extracellular Ca2+, the GnRH-activated channel has a unit slope conductance of 8.0 +/- 2.6 pS (range 4-14 pS). The channel conductance is increased to 13.6 +/- 2.4 pS when the external medium contains 95 mM Ba2+ as the charge carrier. GnRH action appears to be mediated through an internal messenger system, since GnRH does not need to be in direct contact with these channels in order to cause their opening. This internal messenger system is unlikely to be Ca2+ itself. In addition, two other voltage-dependent outward-current channels have also been detected, both of which are permeable to K+, but differentiated in the cell-attached recording mode by widely different conductance values of 20-30 and 100-120 pS, respectively, and a reversal potential of -90 to -100 mV. The higher conductance channel is sensitive to internal Ca2+, and its probability of opening is increased in the presence of GnRH.

Animals↗

A patch-clamp study of potassium currents in resting and acetylcholine-stimulated mouse submandibular acinar cells.

Salivary acini were enzymatically isolated from submandibular glands of adult male mice. The patch-clamp technique was employed to investigate the conductive properties and activities of a large-conductance K+ channel in both cell-attached and in excised patches of basolateral acinar cell membranes. In excised, inside out, patches with identical high-K+ solutions (145 mM-KCl) on either side of the membrane the current-voltage (I-V) plot was linear. The mean single-channel conductance was 245 +/- 4.8 ps with a single-channel permeability of 4.6 X 10(-13) cm3 s-1. At Ca2+ concentrations of 10(-9)-10(-8) M bathing the intracellular membrane face the channel was exquisitely sensitive to changes in transmembrane potential, i.e. voltage sensitive. At 10(-7) M-Ca the channel was almost always open and displayed little sensitivity to voltage. Single-channel currents were recorded in cell-attached patches. When the recording pipettes contained the high-K+ solution the I-V plots were linear and the mean single-channel conductance and permeability almost identical to that in the excised patches. The mean spontaneous resting potential of the acinar cells bathed in physiological saline (140 mM-NaCl, 4.5 mM-KCl) was -43 +/- 1.8 mV. The voltage sensitivity of the in situ K+ channel was very similar to that recorded in excised patches at 10(-9)-10(-8) M-Ca. In experiments designed to reproduce the physiological ionic gradients across the patch membrane pipettes were filled with the high-Na+ solution. The I-V plot was not linear but showed pronounced rectification at negative membrane potentials. The channel is K+ selective and the extrapolated reversal potential was close to -90 mV. The single-channel conductance at the spontaneous resting membrane potential was about 35 pS. The single-channel permeability was however only slightly reduced at 4.29 X 10(-13) cm3 s-1. It was demonstrated that current flow through the open K+ channel could be accurately modelled using constant field electrodiffusion theory. Continuous in situ recordings before and after application of the agonist acetylcholine to the solution bathing the acini revealed that acetylcholine stimulation is associated with a marked increase in the frequency and duration of K+ currents in the patch membrane. The increased current activity in the patch membrane during acetylcholine application must be mediated via an intracellular second messenger and was very similar to that observed in the excised patches on increasing ionized Ca2+ concentrations from 10(-8) to 10(-7) M.(ABSTRACT TRUNCATED AT 400 WORDS)

Acetylcholine↗

How do patch clamp seals form? A lipid bleb model.

Individual ion channels are electrically isolated and studied in living cells with the tight patch voltage clamp method. Channels are identified, categorized, and sometimes named on the basis of the biophysical properties obtained with this method. Although it is usually presumed that these recordings are from native, undisturbed membrane, the physical basis of this technique is not well established. Observations that lipid blebs readily form when suction is applied to patch clamp electrodes suggest that many single channel recordings are from ion channels in these blebs.

Animals↗

[Computer analysis of single channel current record by extracellular patch clamp].

Neher and Sakmann had provided the presence of the channel protein by the direct measurement of single channel current from excitable membrane in 1976. The advantage of this method "patch clamp" is to isolate a small part of membrane and pick up electrical excitability. In order to record single channel current the seal resistance between patch electrode and cell membrane must be at least more than gigaohm. To improve this recording condition enzyme treated cell or culture cell is necessary since fibroblast which attaches to a target cell disturbs gigaseal formation. In this study we use the computer to improve the single channel current recorded by low seal resistance.

Electric Conductivity↗

Phenytoin preferentially inhibits L-type calcium currents in whole-cell patch-clamped cardiac and skeletal muscle cells.

The effect of the anticonvulsant diphenylhydantoin (phenytoin) was tested on the inward calcium currents of whole-cell patch-clamped cells from rat and human muscles and from frog atrium. A concentration of 10 microM phenytoin was required to obtain a threshold inhibitory effect and, even with high concentrations (100 microM), the inhibition was not complete. In skeletal muscle (rat and human cells in culture), phenytoin (30 microM) exerted a more potent effect on the high-threshold calcium current (ICa,L inhibition: 53 +/- 6% mean +/- SDn-1) rather than on the low-threshold one (ICa,T inhibition: 16 +/- 10%). Similar results were obtained on dissociated frog atrial cells. These data are to be contrasted with those previously reported on neuronal cells, where specific inhibition of ICa,T was reported. Thus, the action of phenytoin appears to be different in muscle and nerve so that phenytoin does not appear to be a specific inhibitor of ICa,T.

Animals↗

Effects of alanine on insulin-secreting cells: patch-clamp and single cell intracellular Ca2+ measurements.

The effects of alanine, glucose and tolbutamide on insulin-secreting cells (RINm5F) have been investigated using patch-clamp and single cell intracellular Ca2+ measurements. When directly challenged with the amino acid L-alanine (2-10 mM) the cells underwent a sharp depolarization, which led to the generation of Ca2+ spike potentials and an increase in [Ca2+]i. The L-alanine-induced depolarization was associated with a net inward membrane current but no measurable change in the resistance of the cell. The latter effect was found to be in contrast to the actions of glucose (5-10 mM) and tolbutamide (100 microM), both of which depolarized cells and raised [Ca2+]i by an increase in the input resistance of the cell membrane, due to the closure of ATP-sensitive potassium channels. In the complete absence of external Na+ (by replacement with 140 mM NMDG+), L-alanine had no effects on either the membrane potential or [Ca2+]i. Similarly, replacing Na+ with NMDG+ in the continued presence of the amino acid resulted in a repolarization of the membrane and an attenuation of the L-alanine-induced rise in [Ca2+]i. The Na+ channel blocker TTX (1-2 microM) had no effects on the alanine-evoked electrical activity. Exchange of the L-form of the amino acid with the D-stereoisomer had similar actions to those of removing external Na+, since D-alanine had no effects on the membrane potential or [Ca2+]i. The actions of L-alanine were also found to be mimicked by the N-methylated amino acid analogue methylamino isobutyric acid (MeAIB) (2-10 mM), suggesting that the A-type electrogenic amino acid cotransport system operates in the RINm5F insulin-secreting cell line.

Alanine↗

[Use of isolated myocytes and the patch clamp technic in pharmacological studies].

Effects of palmitylcarnitine, a toxic metabolite of ischaemia, on the electrophysiological properties of single ventricular myocytes of guinea pig were studied by means of patch clamp technique. Cells were enzymatically isolated by perfusing the heart with Ca-free Tyrode solution containing collagenase enzyme. Before experimentation, cells were allowed to recover in a regenerating solution for at least one hour at room temperature. An aliquot of the cell suspension was placed in a small (0.5 ml volume) chamber mounted on the stage of an inverted microscope. After a settling period of 10 minutes, the cells were superfused with Tyrode solution at a rate of 2 to 4 ml/min. Bath temperature was maintained at 35 degrees C. Patch electrodes were fabricated from glass capillary tubes. The electrodes having resistances of 2 to 4 M were connected to a LIST EPC-7 voltage clamp amplifier. The passive parameters (membrane resistance, time constant, capacitance), and resting and action potentials of the cells were recorded in current clamp mode, while the ionic currents (inward calcium, outward potassium) were recorded in voltage clamp mode. Palmitylcarnitine at 10(-6) M concentration increased the membrane resistance, time constant, and depolarized the cell membrane which was accompanied by a marked prolongation of the action potential duration. Under the effect of the drug, the outward potassium current responsible for the repolarization was decreased, while the inward calcium current responsible for the plateau phase was significantly increased mainly at positive membrane potentials. The steady-state activation and inactivation curves were shifted to less negative potentials. The results indicate that the changes in the membrane electrical properties play an important role in the development of the well-known arrhythmogenic effect of palmitylcarnitine.

Action Potentials↗

A patch-clamp study of the ionic selectivity of the large conductance, Ca-activated chloride channel in muscle vesicles prepared from Ascaris suum.

Plasma membrane vesicles prepared from the bag region of the somatic muscle cell of the parasite Ascaris suum contain a large conductance, voltage-sensitive, calcium-activated chloride channel. The ability of this channel to conduct a variety of anions has been investigated using the patch-clamp technique on isolated inside-out patches of muscle membrane. Symmetrical Cl solutions (140 mM) produced single-channel I/V plots with reversal potentials of 0 mV, substitution of bath Cl by 140 mM NO3, Br and I caused depolarizing shifts in the reversal potentials. Replacement of the internal Cl by F (140 mM) caused a large hyperpolarizing shift in the reversal potential. The channel displayed a permeability sequence of I > Br = NO3 > Cl > F which differed from the corresponding conductance sequence Cl > NO3 = Br = I > F. The ionic environment within the channel pore has been investigated using Reuter and Stevens (1980) plots to describe the selectivity and "fluidity" of the channel pore. In addition, the approach of Wright and Diamond (1977) was employed to estimate the number of cationic binding sites within the channel pore. The channel is relatively fluid but the number of cationic binding sites varies inversely with the ionic radius of the anion from 2.15 for F to 0.89 for the large planar anion NO3.

Animals↗

Tonic inhibition of neuronal calcium channels by G proteins removed during whole-cell patch-clamp experiments.

The barium current through voltage-dependent calcium channels was recorded from cultured rat cortical neurons with the whole-cell configuration of the patch-clamp technique. The maximal current evoked by depolarising pulses from -80 mV to 0 mV was divided into inactivating and non-inactivating fractions. During the first minutes of whole-cell recording, the amplitude of the inactivating fraction increased from less than 0.1 nA to an average value of 1 nA, whereas the amplitude of the non-inactivating component remained essentially the same. This increase in amplitude was prevented when the "perforated-patch technique" was used, suggesting that some intracellular factor that inhibited the barium current was lost or destroyed during conventional whole-cell experiments. When GTP[gamma-S] or GTP was added to the pipette solution, no increase or only a weak rise of the inactivating current was seen, whereas GDP[beta-S] accelerated its increase. The results suggest that some of the calcium channels expressed in cultured cortical neurons are inhibited by a G protein even in the absence of added neurotransmitter. The current increase observed during whole-cell recordings may be due to a loss of intracellular GTP and the subsequent inactivation of an inhibitory G protein.

Animals↗

Luminal non-specific cationic channels in cultured strial marginal cells of guinea pig and gerbil as determined by patch clamp technique.

Using primary cultures of marginal cells of stria vascularis from guinea pig and gerbil, ionic channels located on the luminal membrane were investigated by means of patch clamp technique. Recordings were performed in cell-attached and inside-out configurations. In cell-attached configuration, single channel activity was identified with a conductance of about 25 pS. I-V curve was linear. The probability of opening was increased upon depolarization. Up to 7 channels could be present in the same patch, indicating a rather high density. In inside-out configuration, the reversal potential was 0 mV, suggesting a non-specific cationic channel. These luminal non-specific cationic channels would allow the passive K+ efflux and Na+ influx across the apical membrane of marginal cells. This finding is consistent with the "one-pump" model of strial activity. The present study suggests that culture of strial marginal cells may be a suitable model for in-depth investigation of endolymph physiology.

Animals↗