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PubMed2001

Pharmacological discrimination between effects of carbamazepine on hippocampal basal, Ca(2+)- and K(+)-evoked serotonin release.

To elucidate mechanisms of hippocampal serotonin release and possible mechanisms of clinical action of carbamazepine (CBZ), we determined interaction between antagonists of N-type (omega-conotoxin GVIA:GVIA), P-type (omega-agatoxin IVA:IVA) Ca(2+) channels, Na(+) channel (tetrodotoxin: TTX) and CBZ on hippocampal basal, Ca(2+)- and K(+)-evoked serotonin releases, using microdialysis in freely moving rats. Basal release was reduced by TTX, GVIA and IVA (GVIA>IVA). Ca(2+)-evoked release was reduced by GVIA but unaffected by TTX and IVA. K(+)-evoked release was reduced by TTX, GVIA and IVA (GVIA<IVA). TTX inhibited actions of IVA and GVIA on respective basal and K(+)-evoked releases, without affecting Ca(2+)-evoked release. Perfusion with 100 microM CBZ (estimated-concentration in hippocampal tissue: 19+/-2 microM) enhanced basal and Ca(2+)-evoked releases, but reduced K(+)-evoked release, whereas 1000 microM CBZ (estimated-concentration in hippocampal tissue: 188+/-16 microM) reduced three types of releases. Under condition of pretreatment with 100 and 1000 microM CBZ, TTX unaffected basal and K(+)-evoked releases. Under condition of pretreatment with 100 microM CBZ, IVA and GVIA unaffected basal and K(+)-evoked releases, respectively, but GVIA reduced basal, Ca(2+)-evoked releases and IVA also reduced K(+)-evoked release. Under condition of pretreatment with 1000 microM CBZ, GVIA unaffected three types of releases, and IVA unaffected basal release but reduced K(+)-evoked release. These findings contribute towards the possible mechanisms of concentration-dependent antiepileptic action of CBZ, which possibly inhibits Na(+) channel related neurotransmitter release mechanisms during K(+)-evoked stage, and simultaneously enhances N-type Ca(2+) channel related basal serotonin release at the resting stage.

Animals↗
PubMed2003

Beta-oxidation of 5-hydroxydecanoate, a putative blocker of mitochondrial ATP-sensitive potassium channels.

5-Hydroxydecanoate (5-HD) inhibits ischaemic and pharmacological preconditioning of the heart. Since 5-HD is thought to inhibit specifically the putative mitochondrial ATP-sensitive K+ (KATP) channel, this channel has been inferred to be a mediator of preconditioning. However, it has recently been shown that 5-HD is a substrate for acyl-CoA synthetase, the mitochondrial enzyme which 'activates' fatty acids. Here, we tested whether activated 5-HD, 5-hydroxydecanoyl-CoA (5-HD-CoA), is a substrate for medium-chain acyl-CoA dehydrogenase (MCAD), the committed step of the mitochondrial beta-oxidation pathway. Using a molecular model, we predicted that the hydroxyl group on the acyl tail of 5-HD-CoA would not sterically hinder the active site of MCAD. Indeed, we found that 5-HD-CoA was a substrate for purified human liver MCAD with a Km of 12.8 +/- 0.6 microM and a kcat of 14.1 s-1. For comparison, with decanoyl-CoA (Km approximately 3 microM) as substrate, kcat was 6.4 s-1. 5-HD-CoA was also a substrate for purified pig kidney MCAD. We next tested whether the reaction product, 5-hydroxydecenoyl-CoA (5-HD-enoyl-CoA), was a substrate for enoyl-CoA hydratase, the second enzyme of the beta-oxidation pathway. Similar to decenoyl-CoA, purified 5-HD-enoyl-CoA was also a substrate for the hydratase reaction. In conclusion, we have shown that 5-HD is metabolised at least as far as the third enzyme of the beta-oxidation pathway. Our results open the possibility that beta-oxidation of 5-HD or metabolic intermediates of 5-HD may be responsible for the inhibitory effects of 5-HD on preconditioning of the heart.

Acyl Coenzyme A↗
PubMed2003

Contribution of Ca2+-dependent conductances to membrane potential fluctuations of medullary respiratory neurons of newborn rats in vitro.

Ca2+-dependent conductances were studied in respiratory interneurons in the brainstem-spinal cord preparation of newborn rats. omega-Conotoxin-GVIA attenuated evoked postsynaptic potentials, spontaneous or evoked inspiratory spinal nerve activity and blocked spike afterhyperpolarization. Furthermore, omega-conotoxin-GVIA augmented rhythmic drive potentials of pre-inspiratory and inspiratory neurons and increased respiratory-related spike frequency of pre-inspiratory cells with no effect on inspiratory hyperpolarization. In contrast, omega-agatoxin-IVA depressed drive potentials of pre-inspiratory and inspiratory neurons and attenuated inspiratory hyperpolarization and spike frequency of pre-inspiratory cells. It did not affect spike shape and exerted only minor, non-significant, attenuating effects on spontaneous or evoked nerve bursts or evoked postsynaptic potentials. Nifedipine diminished drive potentials and spike frequency of pre-inspiratory neurons and shortened drive potentials in some cells. omega-Conotoxin-MVIIC attenuated drive potentials and intraburst firing rate of pre-inspiratory neurons and decreased substantially respiratory frequency. Respiratory rhythm disappeared following combined application of omega-conotoxin-GVIA, omega-conotoxin-MVIIC, omega-agatoxin-IVA and nifedipine. Apamin potentiated drive potentials and abolished spike afterhyperpolarization, whereas charybdotoxin and tetraethylammonium prolonged spike duration without effect on shape of drive potentials. The results show that specific sets of voltage-activated L-, N- and P/Q-type Ca2+ channels determine the activity of particular subclasses of neonatal respiratory neurons, whereas SK- and BK-type K+ channels attenuate drive potentials and shorten spikes, respectively, independent of cell type. We hypothesize that modulation of spontaneous activity of pre-inspiratory neurons via N-, L- and P/Q-type Ca2+ channels is important for respiratory rhythm or pattern generation.

Animals↗
PubMed2002

Ionic basis of the resting membrane potential and action potential in the pharyngeal muscle of Caenorhabditis elegans.

The pharynx of C. elegans is a rhythmically active muscle that pumps bacteria into the gut of the nematode. This activity is maintained by action potentials, which qualitatively bear a resemblance to vertebrate cardiac action potentials. Here, the ionic basis of the resting membrane potential and pharyngeal action potential has been characterized using intracellular recording techniques. The resting membrane potential is largely determined by a K(+) permeability, and a ouabain-sensitive, electrogenic pump. As previously suggested, the action potential is at least partly dependent on voltage-gated Ca(2+) channels, as the amplitude was increased as extracellular Ca(2+) was increased, and decreased by L-type Ca(2+) channel blockers verapamil and nifedipine. Barium caused a marked prolongation of action potential duration, suggesting that a calcium-activated K(+) current may contribute to repolarization. Most notably, however, we found that action potentials were abolished in the absence of external Na(+). This may be due, at least in part, to a Na(+)-dependent pacemaker potential. In addition, the persistence of action potentials in nominally free Ca(2+), the inhibition by Na(+) channel blockers procaine and quinidine, and the increase in action potential frequency caused by veratridine, a toxin that alters activation of voltage-gated Na(+) channels, point to the involvement of a voltage-gated Na(+) current. Voltage-clamp analysis is required for detailed characterization of this current, and this is in progress. Nonetheless, these observations are quite surprising in view of the lack of any obvious candidate genes for voltage-gated Na(+) channels in the C. elegans genome. It would therefore be informative to re-evaluate the data from these homology searches, with the aim of identifying the gene(s) conferring this Na(+), quinidine, and veratridine sensitivity to the pharynx.

4-Aminopyridine↗
PubMed1996

Interaction between the L-type Ca2+ channel and the Ca(2+)-activated K+ channel in the fluctuating myogenic contraction in the rabbit basilar artery.

Ring preparations of the rabbit basilar artery spontaneously developed a fluctuating contraction that was not inhibited by the removal of the endothelium or by blockade of the synthesis or action of neurotransmitters and prostanoids. Nifedipine greatly relaxed the spontaneously-developed contraction. Charybdotoxin, an antagonist of the Ca(2+)-activated K+ channel, converted the fluctuating contraction to a tonic contraction, whereas the ATP-sensitive K+ channel blocker, glibenclamide, had no effect. These results indicate that the increased Ca2+ influx via the L-type Ca2+ channel in the rabbit basilar artery may induce myogenic contraction and consequently activate the Ca(2+)-activated K+ channel, which might lead to the fluctuation of the contraction by feedback regulation of the Ca2+ channel.

Animals↗
PubMed1999

Calcium-activated potassium conductances contribute to action potential repolarization at the soma but not the dendrites of hippocampal CA1 pyramidal neurons.

Evidence is accumulating that voltage-gated channels are distributed nonuniformly throughout neurons and that this nonuniformity underlies regional differences in excitability within the single neuron. Previous reports have shown that Ca2+, Na+, A-type K+, and hyperpolarization-activated, mixed cation conductances have varying distributions in hippocampal CA1 pyramidal neurons, with significantly different densities in the apical dendrites compared with the soma. Another important channel mediates the large-conductance Ca2+-activated K+ current (IC), which is responsible in part for repolarization of the action potential (AP) and generation of the afterhyperpolarization that follows the AP recorded at the soma. We have investigated whether this current is activated by APs retrogradely propagating in the dendrites of hippocampal pyramidal neurons using whole-cell dendritic patch-clamp recording techniques. We found no IC activation by back-propagating APs in distal dendritic recordings. Dendritic APs activated IC only in the proximal dendrites, and this activation decayed within the first 100-150 micrometer of distance from the soma. The decay of IC in the proximal dendrites occurred despite AP amplitude, plus presumably AP-induced Ca2+ influx, that was comparable with that at the soma. Thus we conclude that IC activation by action potentials is nonuniform in the hippocampal pyramidal neuron, which may represent a further example of regional differences in neuronal excitability that are determined by the nonuniform distribution of voltage-gated channels in dendrites.

Action Potentials↗
PubMed1997

Effect of potassium channel modulators on male sexual behavior.

In the adult sexually experienced male rat, the intracerebroventricular (i.c.v.) injection of pinacidil, a KATP channel opener, at the dose of 100-150-300 micrograms/rat worsened the copulatory performance in the presence of a receptive female, whereas the administration of glibenclamide, a KATP channel blocker, at the dose of 0.5 and 3 mg/kg intraperitoneally (i.p.) had an improving effect. These data indicate that KATP channels in target neurons may play an important role in the physiology of male sexual behavior.

Animals↗
PubMed2000

A role for voltage-gated potassium channels in the outgrowth of retinal axons in the developing visual system.

Neural activity is important for establishing proper connectivity in the developing visual system. Tetrodotoxin blockade of sodium (Na(+))-dependent action potentials impairs the refining of synaptic connections made by developing retinal ganglion cells (RGCs), but does not affect their ability to get out to their target. Although this may suggest neural activity is not required for the directed extension of RGC axons, in many species developing RGCs express additional, Na(+)-independent ionic mechanisms. To test whether the ability of RGC axons to extend in a directed fashion is influenced by membrane excitability, we blocked the principal modulators of the neural activity of a neuron, voltage-dependent potassium (Kv) channels. First, we showed that RGCs and their growth cones express Kv channels when they are growing through the brain on the way to their main midbrain target, the optic tectum. Second, a Kv channel blocker, 4-aminopyridine (4-AP), was applied to the developing Xenopus optic projection. Blocking Kv channels inhibited RGC axon extension and caused aberrant routing of many RGC fibers. With the higher doses, <25% of embryos had a normal optic projection. These data suggest that Kv channel activity regulates the guidance of growing axons in the vertebrate brain.

4-Aminopyridine↗
PubMed1996

ATP-regulated K+ channel in mitochondria: pharmacology and function.

Mitochondria from several tissues contain a potassium-specific channel similar to the ATP-regulated K+ (K ATP) channel of the plasma membrane. The mitochondrial channel shares with the plasma membrane K ATP channel the sensitivity to sulfonylurea derivatives and some other blockers as well as to channel openers of diverse chemical character. In contrast to the plasma membrane channel, which is blocked by free ATP, the mitochondrial K ATP channel reconstituted into liposomes requires the ATP-Mg complex for inhibition. The mitochondrial K ATP channel, possibly in a concerted action with other K+ permeability pathways, plays an important role in mitochondrial volume control. Its function in the regulation of the components of the protonmotive force is also suggested.

Adenine Nucleotides↗
PubMed2005

Homogeneous distribution of large-conductance calcium-dependent potassium channels on soma and apical dendrite of rat neocortical layer 5 pyramidal neurons.

Voltage-gated conductances on dendrites of layer 5 pyramidal neurons participate in synaptic integration and output generation. We investigated the properties and the distribution of large-conductance calcium-activated potassium channels (BK channels) in this cell type using excised patches in acute slice preparations of rat somatosensory cortex. BK channels were characterized by their large conductance and sensitivity to the specific blockers paxilline and iberiotoxin. BK channels showed a pronounced calcium-dependence with a maximal opening probability of 0.69 at 10 microm and 0.42 at 3 microm free calcium. Their opening probability and transition time constants between open and closed states are voltage-dependent. At depolarized potentials, BK channel gating is described by two open and one closed states. Depolarization increases the opening probability due to a prolongation of the open time constant and a shortening of the closed time constant. Calcium-dependence and biophysical properties of somatic and dendritic BK channels were identical. The presence of BK channels on the apical dendrite of layer 5 pyramidal neurons was shown by immunofluorescence. Patch-clamp recordings revealed a homogeneous density of BK channels on the soma and along the apical dendrite up to 850 microm with a mean density of 1.9 channels per microm(2). BK channels are expressed either isolated or in clusters containing up to four channels. This study shows the presence of BK channels on dendrites. Their activation might modulate the shape of sodium and calcium action potentials, their propagation along the dendrite, and thereby the electrotonic distance between the somatic and dendritic action potential initiation zones.

Animals↗
PubMed1995

Mechanism of K+ channel block by verapamil and related compounds in rat alveolar epithelial cells.

The mechanism by which the phenylalkylamines, verapamil and D600, and related compounds, block inactivating delayed rectifier K+ currents in rat alveolar epithelial cells, was investigated using whole-cell tight-seal recording. Block by phenylalkylamines added to the bath resembles state-dependent block of squid K+ channels by internally applied quarternary ammonium ions (Armstrong, C.M. 1971. Journal of General Physiology. 58:413-437): open channels are blocked preferentially, increased [K+]o accelerates recovery from block, and recovery occurs mainly through the open state. Slow recovery from block is attributed to the existence of a blocked-inactivated state, because recovery was faster in three situations where recovery from inactivation is faster: (a) at high [K+]o, (b) at more negative potentials, and (c) in cells with type l K+ channels, which recover rapidly from inactivation. The block rate was used as a bioassay to reveal the effective concentration of drug at the block site. When external pH, pHo, was varied, block was much faster at pHo 10 than pHo 7.4, and very slow at pHo 4.5. The block rate was directly proportional to the concentration of neutral drug in the bath, suggesting that externally applied drug must enter the membrane in neutral form to reach the block site. High internal pH (pHi 10) reduced the apparent potency of externally applied phenylalkylamines, suggesting that the cationic form of these drugs blocks K+ channels at an internal site. The permanently charged analogue D890 blocked more potently when added to the pipette than to the bath. However, lowering pHi to 5.5 did not enhance block by external drug, and tertiary phenylalkylamines added to the pipette solution blocked weakly. This result can be explained if drug diffuses out of the cell faster than it is delivered from the pipette, the block site is reached preferentially via hydrophobic pathways, or both. Together, the data indicate the neutral membrane-bound drug blocks K+ channels more potently than intracellular cationic drug. Neutral drug has rapid access to the receptor, where block is stabilized by protonation of the drug from the internal solution. In summary, externally applied phenylalkylamines block open or inactivated K+ channels by partitioning into the cell membrane in neutral form and are stabilized at the block site by protonation.

Animals↗
PubMed2001

Effect of ATP sensitive potassium channel modifiers on antinociceptive effect of metoclopramide.

Metoclopramide, a prokinetic drug, has been documented to produce antinociceptive response in animal models through opioid pathways. Morphine has been shown to act through ATP sensitive potassium channels (KATP) to produce antinociceptive response. However, such a possibility has not been examined for metoclopramide. The present study investigated this using pharmacological tools. Acetic acid induced abdominal constriction assay procedure was utilized to assess antinociception. The results confirmed that metoclopramide has antinociceptive response. Glibenclamide, a KATP channel blocker, pretreatment antagonized this response. Where as, in minoxidil pretreated animals, metoclopramide elicited an enhanced antinociceptive response. Glibenclamide and minoxidil, which are known KATP channel blocker and opener respectively, interfered with metoclopramide antinociception. These finding are suggestive of a role for KATP channels in metoclopramide antinociception in mice.

Adenosine Triphosphate↗
PubMed2004

Blocking effect of lanthanum on delayed-rectifier K+ current in Drosophila neurons.

The delayed-rectifier potassium current (IKDR) is important in regulating neuronal excitability. The authors characterized the neurotoxic effect of lanthanum on IKDR. The conventional whole-cell patch-clamp technique was applied to cultured Drosophila neurons derived from embryonic neuroblasts. IKDR was measured from neurons before and after application of 0.1 mM lanthanum to the external saline. IKDR was smaller in the lanthanum-containing saline (441 +/- 57 pA) than in the control saline (680 +/- 35 pA) (p <.001). Activation and inactivation of IKDR were unchanged by lanthanum. Because these results suggest that lanthanum acts as a potent blocker of IKDR, neuronal excitability may be altered during lanthanum neurotoxicity.

Animals↗
PubMed1993

Functional colocalization of calcium and calcium-gated potassium channels in control of transmitter release.

We examined, using physiological and morphological techniques, the distribution of Ca(2+)-gated K+ (gKca) channels relative to the location of Ca2+ channels and transmitter release sites at the frog neuromuscular junction (NM). Charybdotoxin (ChTx) and iberiotoxin, blockers of gKca channels with large conductances, increase transmitter release at the frog NMJ. Intracellular Ca2+ buffers with rapid binding kinetics, dimethyl BAPTA and BAPTA, prevented the effect of ChTx, but EGTA, a Ca2+ buffer with similar affinity for Ca2+ but slower binding kinetics, did not. Dimethyl BAPTA and BAPTA, but not EGTA, caused a temporary increase in transmitter release. Labeling of gKca channels with ChTx-biotin revealed a series of bands located at the sites of Ca2+ channels, but this labeling did not occur in denervated preparations. Cross sections of NMJs revealed that gKca channels are clustered in the presynaptic membrane facing the postsynaptic membrane. We conclude that gKca channels are strategically clustered at the neurotransmitter release sites, where they can be quickly activated by Ca2+ entering the terminal.

Animals↗
PubMed1997

Capacitative Ca2+ entry associated with alpha1-adrenoceptors in rat aorta.

In rat aorta, depletion of internal Ca2+ stores by addition of noradrenaline (1 microM) induces a biphasic response (an initial phasic response and a tonic one) mediated by two different intracellular Ca2+ pools. This response cannot be repeated, suggesting a depletion of internal Ca2+ stores sensitive to noradrenaline. In absence of the agonist, this depletion is the signal for the entry of extracellular Ca2+, not only to refill the stores but also, under our experimental conditions, to activate the contractile proteins thus inducing an increase in the resting tone (IRT) that constitutes functional evidence of this Ca2+ entry. The ionic channels involved in the mechanism of the IRT have been studied in the present work. The fact that the addition of nimodipine (10(-15)-10(-11) M) selectively inhibits the IRT suggests that this mechanical response is mediated by Ca2+ influx through dihydropyridine-sensitive Ca2+ channels. Moreover, the inhibitory action of nimodipine is attenuated by glibenclamide (10 microM). Cromakalim (10(-10)-10(-6) M) also inhibits the IRT concentration dependently, and this inhibition is antagonized by glibenclamide (10 microM). These results relate the ATP-dependent K+ channels to the mechanism of the IRT. The refilling of the two internal Ca2+ compartments sensitive to noradrenaline was, like the IRT, altered in presence of the compounds tested, since the subsequent contractile response to noradrenaline was decreased. The present results suggest that nimodipine treatment inhibits the refilling of the Ca2+ compartment responsible for the tonic contraction induced by noradrenaline in Ca2+-free medium, whereas the refilling of the Ca2+ pool responsible for the phasic response to noradrenaline remained unaltered. Both the phasic and tonic responses to noradrenaline in Ca2+-free medium decreased after treatment with cromakalim. We can therefore assume that the refilling of both Ca2+ compartments sensitive to noradrenaline was inhibited. In conclusion, these results are consistent with the contraction of the rat aorta in response to noradrenaline in Ca2+-free medium consisting of an initial phasic response and a tonic one. The former is due to the release of internal Ca2+ from a compartment refilled through a special channel that is cromakalim but not dihydropyridine sensitive. The tonic response is due to Ca2+ release from another compartment refilled through a cromakalim- and dihydropyridine-sensitive Ca2+ channel. The Ca2+ entry through this latter channel intervenes in the IRT observed during the refilling of these stores previously depleted by noradrenaline, and the opening state of this channel is also modulated by ATP-dependent K2+ channels.

Animals↗
PubMed1998

A discriminant block among K+ channel types by phenytoin in neuroblastoma cells.

The action of the anticonvulsant drug phenytoin on K+ channels was investigated in neuroblastoma cells (N2A) by using the single-channel patch-clamp technique. N2A cells expressed three types of delayed rectifier K+ channels, which were found to have a conductance of 10-20 pS in a 'physiological' K+ gradient. When added to the external solution at concentrations ranging between 1 and 200 microM, phenytoin decreased single channel activity, whereas the unitary current amplitude was unaffected in all three types of channels. The open probability of the biggest channel decreased, according to an exponential distribution of open and closed times, from 40% in control conditions to 10% in the presence of 50 microM phenytoin (Vm=40 mv). The reduction in the open-channel probability was concentration-dependent with a IC50 = 27.2+/-0.9 microM. A transient type of K channel was identified that was affected by cumulative inactivation and had a conductance of a mean value equal to 26 pS. Finally, a voltage-and Ca2+-dependent K+ channel with a unitary conductance of 95 pS was recorded. Both the channel's amplitude and kinetics were unaffected by phenytoin. These results confirm the phenytoin effect on K+ currents and suggest that the drug may be considered a selective blocker of delayed rectifier K+ channels.

Animals↗
PubMed2001

Membrane resonance and subthreshold membrane oscillations in mesencephalic V neurons: participants in burst generation.

Trigeminal mesencephalic (Mes V) neurons are critical components of the circuits controlling oral-motor activity. The possibility that they can function as interneurons necessitates a detailed understanding of the factors controlling their soma excitability. Using whole-cell patch-clamp recording, in vitro, we investigated the development of the ionic mechanisms responsible for the previously described subthreshold membrane oscillations and rhythmical burst discharge in Mes V neurons from rats ages postnatal day (P) 2-12. We found that the oscillation amplitude and frequency increased during development, whereas bursting emerged after P6. Furthermore, when bursting was initiated, the spike frequency was largely determined by the oscillation frequency. Frequency domain analysis indicated that these oscillations emerged from the voltage-dependent resonant properties of Mes V neurons. Low doses of 4-aminopyridine (<100 microm) reduced the oscillations and abolished resonance in most neurons, suggesting that the resonant current is a steady-state K(+) current (I(4-AP)). Sodium ion replacement or TTX reduced substantially the oscillations and peak amplitude of the resonance, suggesting the presence of a persistent Na(+) current (I(NaP)) that functions to amplify the resonance and facilitate the emergence of subthreshold oscillations and bursting.

4-Aminopyridine↗