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PubMed1998

Voltage-operated potassium currents in the somatic membrane of rat dorsal root ganglion neurons: ontogenetic aspects.

Whole-cell transmembrane potassium currents were studied in somatic membrane of freshly isolated rat dorsal root ganglion neurons. We defined three types of potassium currents, which were separated on the basis of their different potential dependence of activation and sensitivity to external tetraethylammonium and 4-aminopyridine. The potential dependence of kinetic and steady-state properties of a fast inactivating potassium current, a slow inactivating potassium current and a non-inactivating delayed rectifier current were described by the Hodgkin-Huxley equations. A transient fast inactivating potassium current was activated at the most negative membrane potentials and was not reduced in the presence of 10 mM tetraethylammonium in the external solution. 4-Aminopyridine (2 mM) caused an 80% inhibition of this current. The activation of the fast inactivating potassium current was properly described by fitting a single exponent raised to the fourth power. The time constant of activation changed from 4 to 1 ms in the voltage range between -30 and +40 mV. The time constant of inactivation decreased from 35 to 15 ms over the same range of potentials. Parameters for the fit of a Boltzmann equation to mean values for steady-state activation were V1/2=-20mV, k=11.8mV, and for steady-state inactivation V1/2= -85 mV, k=-9.8 mV. A transient slow inactivating potassium current had an activation threshold between -40 and -30 mV. At 2 mM 4-aminopyridine, the depression of the slow potassium current was 55%. The extracellular application of 10 mM tetraethylammonium was less effective and evoked a 40% reduction. The activation of the slow inactivating potassium current was also described by a single exponential function raised to the fourth power. The time constant of activation decreased from 12 ms at a membrane potential of -10 mV to 4 ms at the potential of 60 mV. The inactivation of slow inactivating potassium current was described by two exponents. The time constant for the fast exponent ranged from 300 ms at -20 mV to 160 ms at +60 mV. The slower exponent was also potential dependent and its time constant ranged from approximately 2600 to 1600 ms over the same potentials. Parameters for the Boltzmann equation fittings to mean values were V1/2= -12.8 mV, k=13.4 mV and V1/2= -54.6 mV, k= -12 mV for steady-state activation and inactivation, respectively. A non-inactivating delayed rectifier potassium current was activated at the most positive membrane potentials. This non-inactivating current did not change in the presence of 4-aminopyridine. Extracellular tetraethylammonium (10 mM) caused a 70% reduction of this current. The activation of the non-inactivating potassium current was described by one exponent raised to the fourth power. The time constant for activation ranged from 85 ms at -5 mV to 30 ms at 45 mV. No time-dependent inactivation was observed during 15-s testing potentials in the voltage range between 10 and +60 mV. The activation behavior was characterized by V1/2=15.3 mV, k=12.5 mV. The densities of these potassium currents were studied for three groups of animals: one, five to six and 14-15 days of postnatal development. Fifty cells were examined in each age group. All three types of potassium currents were found in each investigated neuron. The mean densities of slow and fast inactivating potassium currents increased during ontogenetic development. The densities of non-inactivating delayed rectifier potassium current decreased in the first week of ontogenetic development and did not change thereafter.

4-Aminopyridine↗
PubMedDate not supplied

Nootropic agent vinpocetine blocks delayed rectified potassium currents more strongly than high-threshold calcium currents.

A two-microelectrode potential clamping method was used on isolated common snail neurons to measure high-threshold Ca2+ and delayed rectified K+ currents. Addition of the nootropic agent vinpocetine (VPC) to the bathing solution rapidly and reversibly inhibited both types of current. The effects of VPC were dose-dependent and were independent of the test stimulus voltage. Maximum blockade of the Ca2+ current averaged 27% at a VPC concentration of 600 microM. Maximum blockade of the K+ current averaged 76% at a VPC concentration of 30 microM. It is concluded that K+ channels are more likely targets of VPC than Ca2+ channels.

Animals↗
PubMed1992

Effect of charybdotoxin and leiurotoxin I on potassium currents in bullfrog sympathetic ganglion and hippocampal neurons.

The effects of charybdotoxin and leiurotoxin I were examined on several classes of K+ currents in bullfrog sympathetic ganglion and hippocampal CA1 pyramidal neurons. Highly purified preparations of charybdotoxin selectively blocked a large voltage- and Ca(2+)-dependent K+ current (IC) responsible for action potential repolarization (IC50 = 6 nM) while leiurotoxin I selectively blocked a small Ca(2+)-dependent K+ conductance (IAHP) responsible for the slow afterhyperpolarization following an action potential (IC50 = 7.5 nM) in bullfrog sympathetic ganglion neurons. Neither of the toxins had significant effects on other K+ currents (M-current [IM], A-current [IA] and the delayed rectifier [IK]) present in these cells. Leiurotoxin I at a concentration of 20 nM had no detectable effect on currents in hippocampal CA1 pyramidal neurons. This lack of effect on IAHP in central neurons suggests that the channels underlying slow AHPs in those neurons are pharmacologically distinct from analogous channels in peripheral neurons.

Animals↗
PubMed1990

Tedisamil blocks the transient and delayed rectifier K+ currents in mammalian cardiac and glial cells.

The potassium currents in rat and guinea pig ventricular myocytes and mouse astrocytes were studied using tedisamil, a novel antiarrhythmic agent. A 1 to 20 microM dosage of tedisamil caused marked prolongation of the action potential in isolated rat ventricular myocytes, mimicking its reported effects on multicellular rat heart preparations. Under voltage clamp conditions, tedisamil caused a dose-dependent increase in the speed of inactivation of the transient outward K+ current (Ito), the predominant outward current in rat ventricular myocytes. In cardiac myocytes, the tedisamil block was neither use- nor voltage-dependent. The slow reversibility of drug action when applied from the outside, and its effectiveness when applied intracellularly, suggested an internal site of drug action. In guinea pig ventricular myocytes, tedisamil blocked the slowly developing time-dependent delayed rectifier K+ current (IK) over the same concentration range as that found for Ito in the rat myocytes. Tedisamil reduced this current without changing the characteristics of its slow (tau approximately 1 sec) activation. The effects of tedisamil on Ito and IK were independent of the phosphorylation state of the channel, as assessed by the equal effectiveness of the drug in the presence or absence of isoproterenol. Tedisamil also blocked the transient K+ current and the delayed rectifier current (IK) in mouse astrocytes over the same concentration range as that found in the cardiac myocytes and by a process that accelerated (transient K+ current) or mimicked (IK) inactivation. At concentrations of up to 50 microM, tedisamil had little effect on the time-dependent inward rectifier K+ current, or inward calcium current in rat or guinea pig ventricular myocytes.(ABSTRACT TRUNCATED AT 250 WORDS)

Action Potentials↗
PubMed2001

Capsaicin-induced relaxation in rabbit coronary artery.

In the present study mechanism of inhibitory effects of capsaicin on the contractility of rabbit coronary artery were studied by measurement of isometric tension and intracellular Ca2+ concentration. Capsaicin (1 microM to 30 microM) relaxed the coronary artery pre-contracted with prostaglandin (PG) F2alpha (1 microM) in a concentration-dependent manner. The PGF2alpha-induced increase in intracellular Ca2+ concentration was also inhibited. The effects of capsaicin were readily reversed by washing capsaicin from the bath. Capsaicin-induced relaxation was not attenuated by pretreatment with capsazepine (1 microM), a blocker of vanilloid receptor or ruthenium red (1 microM), a blocker of non-selective cation channel. Previous exposure to a high concentration of capsaicin (100 microM) or repeated application of capsaicin did not eliminate the relaxation response to subsequent application of capsaicin. Increasing the external K+ concentration to 80 mM significantly attenuated the capsaicin-induced relaxation with simultaneous change in intracellular Ca2+ concentration. Pretreatment with iberiotoxin (100 nM), a blocker of Ca2+-activated K+ channel, only partially inhibited the capsaicin-induced relaxation. However, application of 4-aminopyridine (4-AP, 1 mM), a blocker of delayed rectifier K+ current significantly inhibited the capsaicin-induced relaxation with concomitant attenuation of the effect on intracellular Ca2+ concentration. These results indicate that capsaicin may have a direct relaxing effect on the smooth muscle contractility, and relaxation may be due to activation of the 4-AP-sensitive, delayed rectifier K+ channels in the rabbit coronary artery.

4-Aminopyridine↗
PubMed1999

Pause induced early afterdepolarizations in the long QT syndrome: a simulation study.

OBJECTIVE: The long QT syndrome (LQTS) is characterized by prolonged repolarization and propensity to syncope and sudden death due to polymorphic ventricular tachycardias such as torsade de pointes (TdP). The exact mechanism of TdP is unclear, but pause-induced early afterdepolarizations (EADs) have been implicated in its initiation. In this study we investigate the mechanism of pause-induced EADs following pacing at clinically relevant rates and characterize the sensitivity of different cell types (epicardial, midmyocardial, and endocardial) to EAD development. METHODS: Simulations were conducted using the Luo-Rudy (LRd) model of the mamalian ventricular action potential (AP). Three cell types--epicardial, midmyocardial (M), and enocardial--are represented by altering the channel density of the slow delayed rectifier current, IKs. LQTS is modelled by enhanced late sodium current (LQT3), or reduced density of functional channels that conduct IKr (LQT2) and IKs (LQT1). The cell is paced 40 times at a constant Basic Cycle Length (BCL) of 500 ms. Following a 1500 ms pause, an additional single stimulus is applied. RESULTS: Our results demonstrate that pause-induced EADs develop preferentially in M cells under conditions of prolonged repolarization. These EADs develop at plateau potentials ('plateau EADs'). Mechanistic investigation shows that prolongation of the plateau phase of the post-pause AP due to a smaller delayed rectifier potassium current, IKs' and enhancement of the sodium-calcium exchange current, INaCa, allows for the reactivation of the L-type calcium current, ICa(L), which depolarizes the membrane to generate the EAD. CONCLUSIONS: APD is a very important determinant of arrhythmogenesis and its prolongation, either due to acquired or congenital LQTS, can result in the appearance of EADs. The formation of pause-induced EADs preferentially in M cells suggests a possible role for these cells in the generation of arrhythmias that are associated with abnormalities of repolarization (e.g., TdP). The ionic mechanism of pause-induced EADs involves reactivation of the L-type calcium current during the prolonged plateau of the post-pause AP.

Action Potentials↗
PubMed1997

Mechanism of enhancement of slow delayed rectifier current by extracellular sulfhydryl modification.

To explore the role of sulfhydryl (SH) groups in the function of cardiac slow delayed rectifier channels, we tested the effects of extracellular thimerosal (TMS, a hydrophilic SH modifier) on slow delayed rectifier current (IKs) induced by human IsK (hIsK) in oocytes and on the native IKs in canine ventricular myocytes. TMS (25 or 50 microM) had similar effects on the two currents: current amplitude increased, and there was an acceleration of activation and a slowing of deactivation. These effects showed little or no reversal after washout of TMS. The effects did not depend on intracellular Ca release or protein kinase activities but could be suppressed by dithiothreitol pretreatment. According to the current model of transmembrane topology, there is no cystein in the extracellular domain of hIsK. A likely candidate for TMS modification is the SH group on another subunit in oocyte cell membrane that interacts with IsK to form a functional channel. To explore the domain of hIsK involved in the interaction, extracellular serines of hIsK were mutated to cysteines at three locations: S37C (close to the transmembrane domain), S4C (close to the NH2-terminus), and S28C (in between). S37C and S28C mutations did not affect channel properties or hIsK response to TMS. On the other hand, S4C mutation reduced current expression even when S4C cRNA was injected at a quantity 50-fold higher than that of the other three proteins. Importantly, the response to TMS was markedly reduced in S4C compared with the other three proteins. Therefore, the NH2-terminus of hIsK may be involved in hIsK interaction with the SH-bearing subunit, and this interaction modulates slow delayed rectifier channel function.

Animals↗
PubMed1988

Characterization of outward currents in a neurosecretory cell acutely isolated from the adult rat.

Hormonal release from neurosecretory cells appears to be regulated in part by ionic currents. Because ethanol was shown to alter the release of melatonin from the cultured pineal gland, the ionic currents present in pineal cells were characterized using the whole-cell patch clamp technique. The macroscopic ionic current observed in standard solutions was dominated by an outward current component. Study of this outward component in a solution without added external Ca2+ revealed the existence of two distinct outward currents. Depolarizing command voltages from a holding potential of -100 mV activated a fast outward current which reached a peak within 20 ms and completely decayed in about 150 ms. The second outward current isolated from a holding potential of -50 mV activated at potentials positive to -20 mV. In the presence of 2 mM external Ca2+ the I-V relationship did not display a region of negative slope conductance suggesting that Ca2+-activated K+ current did not contribute significantly to the outward current. A small Ca2+ inward current was observed when these two outward components were eliminated. These results indicate that acutely dissociated pineal cells display two distinct K+ outward currents: (i) a transient current similar to the A current (IA); and (ii) a slowly activating, sustained current similar to the delayed rectifier (IK). Thus, the characterization of ionic currents in the pineal cell is of importance because they may be a target for acute and chronic ethanol actions.

Animals↗
PubMedDate not supplied

Ionic currents and action potentials in rabbit, rat, and guinea pig ventricular myocytes.

Distinct differences exist in action potentials and ionic currents between rabbit, rat, and guinea pig ventricular myocytes. Data obtained at room temperature indicate that about half of the rabbit myocytes show prominent phase 1 repolarization and transient outward current. Action potentials in guinea pig ventricular myocytes resemble those from rabbit myocytes not exhibiting phase 1 repolarization; and guinea pig myocytes do not develop transient outward current. Rat ventricular action potentials are significantly shorter than those from rabbit and guinea pig ventricular myocytes. Unlike rabbit and guinea pig myocytes, rat ventricular myocytes also exhibit a prominent phase 1 and lack a well defined plateau phase during repolarization. All rat ventricular myocytes exhibit a transient outward current which can be best fitted by a double exponential relation. There are no significant differences between the amplitude, voltage dependence and inactivation kinetics of the inward calcium currents observed in rabbit, rat and guinea pig. The steady-state current-voltage relations between -120 mV and -20 mV, which mostly represent the inward rectifier potassium current are similar in rabbit and guinea pig. The amplitude of this current is significantly less in rat ventricular myocytes. The outward currents activated upon depolarization to between -10 and +50 mV are different in the three species. Only a negligible, or absent, delayed rectifier outward current has been observed in rabbit and rat; however, a relatively large delayed rectifier current has been found in guinea pig. These large interspecies variations in outward membrane currents help explain the differences in action potential configurations observed in rabbit, rat, and guinea pig.

Action Potentials↗
PubMed2005

De novo KCNQ1 mutation responsible for atrial fibrillation and short QT syndrome in utero.

OBJECTIVE: We describe a genetic basis for atrial fibrillation and short QT syndrome in utero. Heterologous expression of the mutant channel was used to define the physiological consequences of the mutation. METHODS: A baby girl was born at 38 weeks after induction of delivery that was prompted by bradycardia and irregular rythm. ECG revealed atrial fibrillation with slow ventricular response and short QT interval. Genetic analysis identified a de novo missense mutation in the potassium channel KCNQ1 (V141M). To characterize the physiological consequences of the V141M mutation, Xenopus laevis oocytes were injected with cRNA encoding wild-type (wt) KCNQ1 or mutant V141M KCNQ1 subunits, with or without KCNE1. RESULTS: Ionic currents were recorded using standard two-microelectrode voltage clamp techniques. In the absence of KCNE1, wtKCNQ1 and V141M KCNQ1 currents had similar biophysical properties. Coexpression of wtKCNQ1+KCNE1 subunits induced the typical slowly activating and voltage-dependent delayed rectifier K(+) current, I(Ks). In contrast, oocytes injected with cRNA encoding V141M KCNQ1+KCNE1 subunits exhibited an instantaneous and voltage-independent K(+)-selective current. Coexpression of V141M and wtKCNQ1 with KCNE1 induced a current with intermediate biophysical properties. Computer modeling showed that the mutation would shorten action potential duration of human ventricular myocytes and abolish pacemaker activity of the sinoatrial node. CONCLUSIONS: The description of a novel, de novo gain of function mutation in KCNQ1, responsible for atrial fibrillation and short QT syndrome in utero indicates that some of these cases may have a genetic basis and confirms a previous hypothesis that gain of function mutations in KCNQ1 channels can shorten the duration of ventricular and atrial action potentials.

Action Potentials↗
PubMed1988

The potassium conductance of the resting squid axon and its blockage by clinical concentrations of general anaesthetics.

1. The effects of some neutral clinical and experimental general anaesthetics on the resting potential of normal squid axons and squid axons exposed to tetrodotoxin and 3,4-diaminopyridine have been studied. 2. Depolarizations of 1-4 mV were produced by all the anaesthetics at 'clinical' concentrations in the normal axon. Larger depolarizations (5-11 mV) were produced by the same anaesthetic concentrations in axons exposed to tetrodotoxin and 3,4-diaminopyridine. 3. The conductance of axons exposed to tetrodotoxin and either tetraethyl-ammonium or 3,4-diaminopyridine in zero Na+, 430 mM-K+ artificial sea water was examined by voltage clamp and AC bridge techniques. 4. The evidence that this conductance is due predominantly to K+ is discussed. 5. Pre-pulse protocols under voltage clamp have been used to show that part of this conductance arises from the incompletely blocked delayed rectifier. 6. Substantial reductions in this conductance are produced by anaesthetics at 'clinical' concentrations. 7. It is concluded that there is a component of the K+ conductance of the resting squid axon other than the Hodgkin-Huxley delayed rectifier which is extremely sensitive to anaesthetics and which to an appreciable extent determines the resting potential.

4-Aminopyridine↗
PubMed1993

PKA-dependent regulation of mKv1.1, a mouse Shaker-like potassium channel gene, when stably expressed in CHO cells.

Potassium (K) channels are important regulators of cellular physiology and can themselves be modulated by phosphorylation. We have investigated the potential protein kinase A (PKA) regulation of mKv1.1, a mouse Shaker-like K channel gene, when it is expressed in stably transfected Chinese hamster ovary (CHO) cell lines. Whole-cell patch-clamp records show that expression of mKv1.1 gives rise to a rapidly activating, sustained K+ current, referred to classically as a delayed rectifier-type current. In order to study the effects of PKA, we compared cell lines transfected with mKv1.1 alone with lines cotransfected with both mKv1.1 and a plasmid encoding a dominant negative mutation in the regulatory subunit of PKA. These mutant regulatory subunits bind to endogenous catalytic subunits of PKA but do not respond to cAMP, thereby causing a chronic reduction in the basal PKA activity in these cells. We found that mKv1.1 current kinetics are unaltered but current density is 3.4-fold higher in the cell lines expressing mutant regulatory subunit than in lines expressing only mKv1.1. RNase protection assays indicate that levels of the specific RNA for mKv1.1 are increased almost twofold in the lines expressing mutant regulatory subunit over the lines expressing mKv1.1 only. Further, the levels of mKv1.1 protein, assayed using an mKv1.1 channel-specific antibody, are increased by almost a factor of 3 between the two types of cell lines. These results suggest that PKA can regulate mKv1.1 channel expression by changing steady-state levels of RNA and by other posttranscriptional mechanisms.

Animals↗
PubMed2003

Effects of tetrandrine on calcium and potassium currents in isolated rat hepatocytes.

AIM: To study the effects of tetrandrine (Tet) on calcium release-activated calcium current (I(CRAC)), delayed rectifier potassium current (I(K)), and inward rectifier potassium currents (I(K1)) in isolated rat hepatocytes. METHODS: Hepatocytes of rat were isolated by using perfusion method. Whole cell patch-clamp techniques were used in our experiment. RESULTS: The peak amplitude of I(CRAC) was -508+/-115 pA (n=15), its reversal potential of I(CRAC) was about 0 mV. At the potential of -100 mV, Tet inhibited the peak amplitude of I(CRAC) from -521+/-95 pA to -338+/-85 pA (P<0.01 vs control, n=5), with the inhibitory rate of 35 % at 10 micromol/L and from -504+/-87 pA to -247+/-82 pA (P<0.01 vs control, n=5), with the inhibitory rate of 49 % at 100 micromol/L, without affecting its reversal potential. The amplitude of I(CRAC) was dependent on extracellular Ca(2+) concentration. The peak amplitude of I(CRAC) was -205+/-105 pA (n=3) in tyrode's solution with Ca(2+) 1.8 mmol/L (P<0.01 vs the peak amplitude of I(CRAC) in external solution with Ca(2+) 10 mmol/L). Tet at the concentration of 10 and 100 micromol/L did not markedly change the peak amplitude of delayed rectifier potassium current and inward rectifier potassium current (P>0.05 vs control). CONCLUSION: Tet protects hepatocytes by inhibiting I(CRAC), which is not related to I(K) and I(K1).

Alkaloids↗
PubMed1999

Expression of Kv3.1 and Kv4.2 genes in developing cerebellar granule cells.

The expression of voltage-gated potassium channels plays an important role in the acquisition of membrane excitability in neurons. We examined the expression pattern of genes in developing cerebellar granule neurons in vivo and in vitro. In situ hybridization of Kv3.1 mRNA demonstrated that the gene was expressed at high levels in the external granule layer (EGL) as well as in the internal granule layer (IGL) at all postnatal stages (P) examined (from P3 to P10). In contrast, Kv4.2 mRNA was detected in the premigratory zone (PMZ) of the EGL, but not in the proliferative zone (PLZ), in addition to the IGL. This indicates that Kv4.2 gene expression initiates in the postmitotic migrating neurons. We also examined the expression of the channel genes in microexplant culture systems. Kv3.1 polypeptide was detected in parallel fibers of granule cells at 2 days in vitro, and the expression continued in later stages. The signal of Kv4.2 protein was very low at 2 days in vitro; however, the number of positive cells and the intensity of the signals were increased at 6 days in vitro. These in vitro observations matched those in vivo and our previous electrophysiological studies in which we demonstrated that delayed- rectifier-type current was predominant in the immature granule cells followed by the later appearance of A-type current. The patterns of K(+) channel expression suggest that sequential expression of these channel genes primarily determines the membrane excitability.

Aging↗
PubMed2004

Probucol aggravates long QT syndrome associated with a novel missense mutation M124T in the N-terminus of HERG.

Patients with LQTS (long QT syndrome) with a mutation in a cardiac ion channel gene, leading to mild-to-moderate channel dysfunction, may manifest marked QT prolongation or torsade de pointes only upon an additional stressor. A 59-year-old woman had marked QT prolongation and repeated torsade de pointes 3 months after initiation of probucol, a cholesterol-lowering drug. We identified a single base substitution in the HERG gene by genetic analysis. This novel missense mutation is predicted to cause an amino acid substitution of Met(124)-->Thr (M124T) in the N-terminus. Three other relatives with this mutation also had QT prolongation and one of them had a prolonged QT interval and torsade de pointes accompanied by syncope after taking probucol. We expressed wild-type HERG and HERG with M124T in Xenopus oocytes and characterized the electrophysiological properties of these HERG channels and the action of probucol on the channels. Injection of the M124T mutant cRNA into Xenopus oocytes resulted in expression of functional channels with markedly smaller amplitude. In both HERG channels, probucol decreased the amplitude of the HERG tail current, decelerated the rate of channel activation, accelerated the rate of channel deactivation and shifted the reversal potential to a more positive value. The electrophysiological study indicated that QT lengthening and cardiac arrhythmia in the two present patients were due to inhibition of I(Kr) (rapidly activating delayed rectifier K(+) current) by probucol, in addition to the significant suppression of HERG current in HERG channels with the M124T mutation.

Animals↗
PubMed1995

On the mechanism of modulation of transient outward current in cultured rat hippocampal neurons by di- and trivalent cations.

1. The mechanisms of Zn2+ modulation of transient outward current (TOC) were studied in cultured rat hippocampal neurons, using the voltage-clamp technique. In the presence of micromolar concentrations of external Zn2+, the voltage dependence of activation and inactivation was shifted to more positive membrane potentials. The gating of TOC was unaltered by internal application of Zn2+. The effect of Zn2+ were not mimicked by external Ca2+, except at very high concentrations (> 10 mM). 2. The modulatory effects of external Zn2+ on TOC gating were not reproduced, antagonized, nor enhanced by lowering external ionic strength, indicating that modulation by Zn2+ does not occur via screening of bulk surface negative charge. 3. A range of other divalent and trivalent metal ions also was studied, and several were found to modulate the transient outward current when added to the extracellular medium. In particular, Pb2+, La3+, and Gd3+ were potent modulators, showing activity in the low micromolar range. Other metal ions were weaker modulators (e.g., Cd2+) or were without activity at the concentrations tested (Fe3+, Cu2+, Ni2+). 4. The same range of ions also was tested on the delayed rectifier K+ current in cultured rat hippocampal neurons. None of the ions studied had significant effects on delayed rectifier gating, although high (> or = 100 microM) concentrations of Pb2+ and La3+ reduced maximal current amplitude, suggesting the possibility of channel block.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Regulation of transmitter release at the squid giant synapse by presynaptic delayed rectifier potassium current.

1. The three-microelectrode voltage clamp technique and pharmacological agents were used to examine the properties and functions of potassium currents in squid giant presynaptic terminals. 2. Outward currents consisted of two components: a slow component which activated over hundreds of milliseconds and was blocked by extracellular application of tetraethylammonium (TEA) ions and a more rapidly activating component which was relatively insensitive to extracellular TEA. 3. The more rapid component was studied in isolation by treating presynaptic terminals with extracellular TEA, as well as tetrodotoxin (to block sodium channel currents) and manganese (to block calcium channel currents). The magnitude of this current component was 1-2 mA cm-2 at 0 mV. Rates of activation and deactivation were voltage dependent and little evidence of inactivation was seen for depolarizations less than several seconds in duration. 4. The reversal potential of the current was -70 to -80 mV in normal saline and became more positive with elevated extracellular potassium concentrations, suggesting that potassium is the primary permeant ion. Accumulation of extracellular potassium appeared to be marked during depolarizations that produced significant activation of the current. 5. Extracellular application of 3,4-diaminopyridine (DAP) blocked the current with an apparent dissociation constant of 7 microM at 0 mV. Intracellular applications of DAP and TEA also were effective in reducing this current. These treatments, but not extracellular TEA application, broadened presynaptic action potentials and increased the magnitude and time-to-peak of postsynaptic currents elicited by the broadened presynaptic action potentials. Postsynaptic currents were a sensitive and linear function of action potential duration; a 30% increase in action potential duration increased postsynaptic current amplitude by 190%. 6. Estimation of the magnitude and time course of the presynaptic calcium current, based on previous measurements of calcium channel gating, indicated that action potential broadening produces a large increase in calcium current magnitude. These calculations predict that a 30% increase in presynaptic action potential duration will increase the peak amplitude of the calcium current by approximately 170% and the total amount of calcium entry by approximately 230%. This implies a linear relationship between transmitter release and calcium entry during an action potential and can be explained by assuming that calcium co-operatively triggers release within intracellular domains that do not overlap.(ABSTRACT TRUNCATED AT 400 WORDS)

4-Aminopyridine↗