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At least 163 records · Page 9Linked to original sources
PubMed1999

N-type calcium channel inactivation probed by gating-current analysis.

N-type calcium channels inactivate most rapidly in response to moderate, not extreme depolarization. This behavior reflects an inactivation rate that bears a U-shaped dependence on voltage. Despite this apparent similarity to calcium-dependent inactivation, N-type channel inactivation is insensitive to the identity of divalent charge carrier and, in some reports, to the level of internal buffering of divalent cations. Hence, the inactivation of N-type channels fits poorly with the "classic" profile for either voltage-dependent or calcium-dependent inactivation. To investigate this unusual inactivation behavior, we expressed recombinant N-type calcium channels in mammalian HEK 293 cells, permitting in-depth correlation of ionic current inactivation with potential alterations of gating current properties. Such correlative measurements have been particularly useful in distinguishing among various inactivation mechanisms in other voltage-gated channels. Our main results are the following: 1) The degree of gating charge immobilization was unchanged by the block of ionic current and precisely matched by the extent of ionic current inactivation. These results argue for a purely voltage-dependent mechanism of inactivation. 2) The inactivation rate was fastest at a voltage where only approximately (1)/(3) of the total gating charge had moved. This unusual experimental finding implies that inactivation occurs most rapidly from intermediate closed conformations along the activation pathway, as we demonstrate with novel analytic arguments applied to coupled-inactivation schemes. These results provide strong, complementary support for a "preferential closed-state" inactivation mechanism, recently proposed on the basis of ionic current measurements of recombinant N-type channels (Patil et al., . Neuron. 20:1027-1038).

Biophysical Phenomena↗
PubMed1998

Fundamental properties of local anesthetics: half-maximal blocking concentrations for tonic block of Na+ and K+ channels in peripheral nerve.

UNLABELLED: Local anesthetics suppress excitability by interfering with ion channel function. Ensheathment of peripheral nerve fibers, however, impedes diffusion of drugs to the ion channels and may influence the evaluation of local anesthetic potencies. Investigating ion channels in excised membrane patches avoids these diffusion barriers. We investigated the effect of local anesthetics with voltage-dependent Na+ and K+ channels in enzymatically dissociated sciatic nerve fibers of Xenopus laevis using the patch clamp method. The outside-out configuration was chosen to apply drugs to the external face of the membrane. Local anesthetics reversibly blocked the transient Na+ inward current, as well as the steady-state K+ outward current. Half-maximal tonic inhibiting concentrations (IC50), as obtained from concentration-effect curves for Na+ current block were: tetracaine 0.7 microM, etidocaine 18 microM, bupivacaine 27 microM, procaine 60 microM, mepivacaine 149 microM, and lidocaine 204 microM. The values for voltage-dependent K+ current block were: bupivacaine 92 microM, etidocaine 176 microM, tetracaine 946 microM, lidocaine 1118 microM, mepivacaine 2305 microM, and procaine 6302 microM. Correlation of potencies with octanol:buffer partition coefficients (logP0) revealed that ester-bound local anesthetics were more potent in blocking Na+ channels than amide drugs. Within these groups, lipophilicity governed local anesthetic potency. We conclude that local anesthetic action on peripheral nerve ion channels is mediated via lipophilic drug-channel interactions. IMPLICATIONS: Half-maximal blocking concentrations of commonly used local anesthetics for Na+ and K+ channel block were determined on small membrane patches of peripheral nerve fibers. Because drugs can directly diffuse to the ion channel in this model, these data result from direct interactions of the drugs with ion channels.

Anesthetics, Local↗
PubMed2001

Progesterone treatment abolishes exogenously expressed ionic currents in Xenopus oocytes.

Fully grown oocytes of Xenopus laevis undergo resumption of the meiotic cycle when treated with the steroid hormone progesterone. Previous studies have shown that meiotic maturation results in profound downregulation of specific endogenous membrane proteins in oocytes. To determine whether the maturation impacts the functional properties of exogenously expressed membrane proteins, we used cut-open recordings from Xenopus oocytes expressing several types of Na(+) and K(+) channels. Treatment of oocytes with progesterone resulted in a downregulation of heterologously expressed Na(+) and K(+) channels without a change in the kinetics of the currents. The time course of progesterone-induced ion channel inhibition was concentration dependent. Complete elimination of Na(+) currents temporally coincided with development of germinal vesicle breakdown, while elimination of K(+) currents was delayed by approximately 2 h. Coexpression of human beta(1)-subunit with rat skeletal muscle alpha-subunit in Xenopus oocytes did not prevent progesterone-induced downregulation of Na(+) channels. Addition of 8-bromo-cAMP to oocytes or injection of heparin before progesterone treatment prevented the loss of expressed currents. Pharmacological studies suggest that the inhibitory effects of progesterone on expressed Na(+) and K(+) channels occur downstream of the activation of cdc2 kinase. The loss of channels is correlated with a reduction in Na(+) channel immunofluorescence, pointing to a disappearance of the ion channel-forming proteins from the surface membrane.

Animals↗
PubMed1999

Voltage-activated currents from adult honeybee (Apis mellifera) antennal motor neurons recorded in vitro and in situ.

Voltage-activated currents from adult honey bee antennal motor neurons were characterized with in vitro studies in parallel with recordings taken from cells in situ. Two methods were used to ensure unequivocal identification of cells as antennal motor neurons: 1) selective backfilling of the neurons with fluorescent markers before dissociation for cell culture or before recording from cells in intact brains, semiintact brains, or in brain slices or 2) staining with a fluorescent marker via the patch pipette during recordings and identifying antennal motor neurons in situ on the basis of their characteristic morphology. Four voltage-activated currents were isolated in these antennal motor neurons with pharmacological, voltage, and ion substitution protocols. The neurons expressed at least two distinct K+ currents, a transient current (IA) that was blocked by 4-aminopyridine (4-5 x 10(-3) M), and a sustained current (IK(V)) that was partially blocked by tetraethylammonium (2-3 x 10(-2) M) and quinidine (5 x 10(-5) M). IA activated above -40 to -30 mV and the half-maximal voltages for steady-state activation and inactivation were -8.8 and -43.2 mV, respectively. IK(V) activated above -50 to -40 mV and the midpoint of the steady-state activation curve was +11.2 mV. IK(V) did not show steady-state inactivation. Additionally, two inward currents were isolated: a tetrodotoxin (10(-7) M)-sensitive, transient Na+ current (INa) that activated above -35 mV, with a maximum around -5 mV and a half-maximal voltage for inactivation of -72.6 mV, and a CdCl2 (5 x 10(-5) M)-sensitive Ca2+ current that activated above -45 to -40 mV, with a maximum around -15 mV. This study represents the first step in our effort to analyze the cellular and ionic mechanisms underlying the intrinsic properties and plasticity of antennal motor neurons.

Algorithms↗
PubMed2004

The therapeutic potential of Na+ and Ca2+ channel blockers in pain management.

Chronic pain affects a large percentage of the population, representing a socio-economic burden. Current treatments are characterised by suboptimal efficacy and/or side effects that limit their use. Among several approaches to treating chronic pain, voltage-sensitive Ca(2+) and Na(+) channels are promising targets. This review evaluates the preclinical evidence that supports the involvement of these targets, with specific attention to those subtypes that appear more strictly correlated with pain generation and sustainment, as well as those compounds that modulate the activity of Ca(2+) and/or Na(+) channels that are currently in clinical development for chronic pain conditions.

Animals↗
PubMed1996

Ionic mechanisms for prolongation of refractoriness and their proarrhythmic and antiarrhythmic correlates.

Drugs that prolong cardiac refractoriness exert antiarrhythmic effects, probably by reducing dispersion of refractoriness and thereby reducing the likelihood of reentrant excitation. This electrophysiologic effect can be achieved in fast-response tissues by sodium channel block or by action potential prolongation; drugs with either attribute can exert antiarrhythmic effects. However, both types of drugs can also cause proarrhythmic effects. For sodium channel blockers, proarrhythmic actions can be attributed to conduction slowing and include increased frequency of episodes of ventricular tachycardia as well as slowing of atrial flutter with 1:1 atrioventricular conduction and increases in ventricular rate. In addition, sodium channel block has been implicated as the mechanism underlying increased mortality with sodium channel blockers in the Cardiac Arrhythmia Suppression Trial (CAST); some data suggest that intercurrent ischemia increases this risk. For drugs that prolong action potentials, torsades de pointes is the most common proarrhythmic syndrome, occurring most often with underlying bradyarrhythmias and hypokalemia. The mechanism(s) underlying normal refractoriness and its modulation by antiarrhythmic drugs, as well as the mechanism(s) underlying these proarrhythmic syndromes, are discussed.

Action Potentials↗
PubMed2002

Recent advances in the modulation of voltage-gated ion channels for the treatment of epilepsy.

Regardless of the voltage-gated ion channel that is targeted in a drug discovery effort for the treatment of epilepsy, two routes have been followed historically: 1). a compound initially, and often surreptitiously, discovered due to activity in animal seizure models is further optimized by medicinal chemistry, or 2). a molecular target is identified based on the phenotype of transgenic animals, or linkage studies from humans with the disease, and compounds are then investigated within a mechanistic framework. Antagonists of voltage-gated sodium channels have been pursued utilizing primarily the first approach; many of these compounds also have significant activity at other ion channels. Both approaches have been utilized to discover voltage-gated calcium channel antagonists, although most efforts to date have used the first approach. Several spontaneous mutant mice and transgenic animals have been utilized to probe the role of the numerous voltage-gated calcium channel subunits and their isoforms as potential molecular targets. Compounds that open or prolong the opening of voltage-gated potassium channels have been discovered using the first approach, with a detailed understanding of the molecular target and mechanism of action coming to light several years later. Genetic evidence from humans is limited to relatively rare forms of epilepsy, and transgenic animals with interesting phenotypes do not always translate into good molecular targets in humans. No clinically-useful antiepileptic drug (AED) has been developed to date that specifically interacts with one, or even one class, of ion channels to produce a therapeutic effect. The tools now exist to search for potent, selective, and safe ion channel modulators for the treatment of epilepsy. This review seeks to summarize the most recent pre-clinical and clinical efforts focused on voltage-gated ion-channels for the development of AEDs.

Animals↗
PubMed2002

Differential blockade of neuronal voltage-gated Na(+) and K(+) channels by antidepressant drugs.

The effects of a range of antidepressants were investigated on neuronal voltage-gated Na(+) and K(+) channels. With the exception of phenelzine, all antidepressants inhibited batrachotoxin-stimulated 22Na(+) uptake, most likely via negative allosteric inhibition of batrachotoxin binding to neurotoxin receptor site-2 on the Na(+) channel. Imipramine also produced a differential action on macroscopic Na(+) and K(+) channel currents in acutely dissociated rat dorsal root ganglion neurons. Imipramine produced a use-dependent block of Na(+) channels. In addition, there was a hyperpolarizing shift in the voltage-dependence of steady-state Na(+) channel inactivation and slowed repriming kinetics consistent with imipramine having a higher affinity for the inactivated state of the Na(+) channel. At higher concentrations, imipramine also blocked delayed-rectifier and transient outward K(+) currents in the absence of alterations to the voltage-dependence of activation or the kinetics of inactivation. These actions on voltage-gated ion channels may underlie the therapeutic and toxic effects of these drugs.

Algorithms↗
PubMed2002

Postnatal development of membrane excitability in taste cells of the mouse vallate papilla.

The mammalian peripheral taste system undergoes functional changes during postnatal development. These changes could reflect age-dependent alterations in the membrane properties of taste cells, which use a vast array of ion channels for transduction mechanisms. Yet, scarce information is available on the membrane events in developing taste cells. We have addressed this issue by studying voltage-dependent Na+, K+, and Cl- currents (I(Na), I(K), and I(Cl), respectively) in a subset of taste cells (the so-called "Na/OUT" cells, which are electrically excitable and thought to be sensory) from mouse vallate papilla. Voltage-dependent currents play a key role during taste transduction, especially in the generation of action potentials. Patch-clamp recordings revealed that I(Na), I(K), and I(Cl) were expressed early in postnatal development. However, only I(K) and I(Cl) densities increased significantly in developing Na/OUT cells. Consistent with the rise of I(K) density, we found that action potential waveform changed markedly, with an increased speed of repolarization that was accompanied by an enhanced capability of repetitive firing. In addition to membrane excitability changes in putative sensory cells, we observed a concomitant increase in the occurrence of glia-like taste cells (the so called "leaky" cells) among patched cells. Leaky cells are likely involved in dissipating the increase of extracellular K+ during action potential discharge in chemosensory cells. Thus, developing taste cells of the mouse vallate papilla undergo a significant electrophysiological maturation and diversification. These functional changes may have a profound impact on the transduction capabilities of taste buds during development.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed2006

Cu2+ (1,10 phenanthroline)3 is an open-channel blocker of the human skeletal muscle sodium channel.

The formation of disulfide bridges is a classical approach used to study the mobility, proximity and distances of residues in a variety of proteins, including ligand- and voltage-gated ion channels. We performed patch-clamp studies to investigate the interaction of a pair of cysteines introduced into the human skeletal muscle voltage-gated Na+ channel (hNa(v)1.4) using the oxidation catalyst, Cu2+ (1,10-phenanthroline)3 (CuPhen). Our experiments resulted in a surprising finding, a reversible current inhibition of the mutant I1160C/L1482C containing two cysteines in the D3/and D4/S4-S5 loops, subjected to oxidative cross-linking in the presence of CuPhen. We report here that CuPhen is an open channel blocker of both mutant and wild-type (WT) hNa(v)1.4 channels, however, for WT channels a more than 10-fold higher concentration was needed to induce the same effect. Moreover, 1,10-phenanthroline was capable of blocking Na+ channels in the absence of Cu2+ ions. Our results indicate a use- and voltage-dependent binding and unbinding of CuPhen, reminiscent of the lidocaine quaternary derivative QX-314 and the neurotoxin batrachotoxin. Care should be taken when using CuPhen as an oxidizing reagent in cross-linking experiments, since it may directly affect channel activity. Our results identify CuPhen (and phenantroline) as a novel use-dependent inhibitor of Na+ channels, a mechanism that is shared by drugs widely used in the treatment of epilepsy, neuropathic pain, cardiac arrhythmia and myotonia. We hypothesize that I1160C in D3/S4-S5 and the corresponding L1482C mutation in D4/S4-S5 could allosterically affect a binding site located in the inner pore region of the channel.

Animals↗
PubMed2002

The involvement of sodium and calcium ions in the release of amino acid neurotransmitters from mouse cortical slices elicited by hyperforin.

Hyperforin is currently considered to be the major active antidepressant constituent of the medicinal herb St. John's wort (Hypericum perforatum L.). The mechanism of action however, is still largely unknown, although the involvement of sodium and calcium has been recently inferred. In the present study hyperforin (5 microM) significantly potentiated the release of endogenous aspartate and glutamate from mouse cortical slices when stimulated by veratridine or potassium. Hyperforin (5 microM) also stimulated the release of aspartate, glutamate, serine, glycine and GABA when perfused on its own. Perfusion of the sodium channel blocker, tetrodotoxin (TTX) inhibited the effect of hyperforin, whereas removal of extracellular calcium potentiated the effect. Our observations suggests that hyperforin increases the overflow of neurotransmitters from mouse cerebral cortex possibly through facilitating the entry of sodium into the neurone which leads to the release of calcium from intracellular stores.

Animals↗
PubMed2005

Migraine prophylactic drugs work via ion channels.

In recent decades, the concept of a vascular origin of migraine has been replaced by theories based on a neuronal pathophysiology. These theories all involve rapid changes in the functioning of the brain, particularly the brain stem, and the trigeminal nerves. While such paroxysmal changes in function could be the result of altered synaptic transmission, or other physiological changes, they could also be due to changes in the function of voltage-regulated sodium and calcium ion channels. Support for this view of migraine as a channelopathy comes from an examination of the likely mechanism of action of migraine prophylactic drugs. It is the present hypothesis that most of the widely used drugs for migraine prevention work by inhibiting the function of one or both of these ion channels. A review of the laboratory research done on most of the commonly used migraine prophylactic drugs, divided into five classes, reveals that they all may work on sodium channels, calcium channels, or both. If this is the common mechanism of action of migraine prophylactics, it should lead toward the development of more effective prophylactic drugs.

Brain↗
PubMed1997

Molecular biology of the long QT syndrome: impact on management.

The long QT syndrome (LQTS) is a familial disease characterized by prolonged ventricular repolarization and high incidence of malignant ventricular tachyarrhythmias often occurring in conditions of adrenergic activation. Recently, the genes for the LQTS inked to chromosomes 3 (LQT3), 7 (LQT2), and 11 (LQT1) were identified as SCN5A, the cardiac sodium channel gene and as HERG and KvLQT1 potassium channel genes. These discoveries have paved the way for the development of gene-specific therapy for these three forms of LQTS. In order to test specific interventions potentially beneficial in the molecular variants of LQTS, we developed a cellular model to mimic the electrophysiological abnormalities of LQT3 and LQT2. Isolated guinea pig ventricular myocytes were exposed to anthopleurin and dofetilide in order to mimic LQT3 and LQT2, respectively. This model has been used to study the effect of sodium channel blockade and of rapid pacing showing a pronounced action potential shortening in response to Na+ channel blockade with mexiletine and during rapid pacing only in anthopleurin-treated cells but not in dofetilide-treated cells. Based on these results we tested the hypothesis that QT interval would shorten more in LQT3 patients in response to mexiletine and to increases in heart rate. Mexiletine shortened significantly the QT interval among LQT3 patients but not among LQT2 patients. LQT3 patients shortened their QT interval in response to increases in heart rate much more than LQT2 patients and healthy controls. These findings suggest that LQT3 patients are more likely to benefit from Na+ channel blockers and from cardiac pacing because they are at higher arrhythmic risk at slow heart rates. Conversely, LQT2 patients are at higher risk to develop syncope under stressful conditions, because of the combined arrhythmogenic effect of catecholamines with the insufficient adaptation of their QT interval. Along the same line of development of gene-specific therapy, recent data demonstrated that an increase in the extracellular concentration of potassium shortens the QT interval in LQT2 patients suggesting that intervention aimed at increasing potassium plasma levels may represent a specific treatment for LQT2. The molecular findings on LQTS suggest the possibility of developing therapeutic interventions targeted to specific genetic defects. Until definitive data become available, antiadrenergic therapy remains the mainstay in the management of LQTS patients, however it may be soon worth considering the addition of a Na+ channel blocker such as mexiletine for LQT3 patients and of interventions such as K+ channel openers or increases in the extracellular concentration of potassium for LQT1 and LQT2 patients.

Action Potentials↗
PubMed1996

Sodium and potassium currents of type I spiral ganglion cells from rat.

Ion channel activity of acutely dissociated type I spiral ganglion cells isolated from rats was investigated using the whole-cell variation of the patch clamp technique. Tetrodotoxin-sensitive sodium current and tetraethylammonium-sensitive potassium current were recorded. With a holding potential of -80 mV, peak sodium currents were generated by depolarizations to membrane potentials more positive than -50 mV. Potassium currents were elicited at membrane potentials more positive than -40 mV. Some cells which did not exhibit sodium current exhibited delayed rectifier potassium currents. Steady-state sodium channel inactivation curve yielded a slope of 12 mV and a half-inactivated potential of -83 mV. Recovery from inactivation of the sodium channel proceeded with a fast and slow time course; recovery began as early as 0.8 ms and proceeded with a time constant of 7.5 ms. It is concluded that type I spiral ganglion cells are endowed with sodium and potassium channels which are responsible for generation and propagation of auditory nerve action potentials.

Action Potentials↗
PubMed2002

Multiple channel interactions explain the protection of sympathetic neurons from apoptosis induced by nerve growth factor deprivation.

We investigated the neuroprotective properties of two M-type K+ channel blockers, linopirdine and its analog XE991, in rat sympathetic neurons deprived of nerve growth factor (NGF). Linopirdine and XE991 promoted sympathetic neuronal survival 48-72 hr after NGF withdrawal in a concentration-dependent manner. Both drugs prevented neuronal apoptosis by blocking the pathway leading to the release of cytochrome c and development of "competence-to-die" after NGF deprivation. Fura-2 Ca2+ imaging showed no significant difference in intracellular free Ca2+ ([Ca2+]i) in the presence or absence of NGF; linopirdine and XE991, on the other hand, caused membrane depolarization and increases in [Ca2+]i. Whole-cell recordings showed that linopirdine and XE991 selectively blocked the M current at neuroprotective concentrations, although they additionally inhibited other K+ currents at high concentrations. Membrane depolarization and [Ca2+]i increases induced by linopirdine and XE991 were blocked by the Na+ channel blocker tetrodotoxin (TTX) or by the L-type Ca2+ channel antagonist nifedipine. TTX and nifedipine also prevented the neuroprotection elicited by linopirdine or XE991. We propose that Na+ channel activation amplifies the membrane depolarization produced by M channel blockade and is essential for subsequent Ca2+ entry via the L-type Ca2+ channel. The interaction of these three classes of ion channels highlights an integrated anti-apoptosis mechanism in sympathetic neurons.

Animals↗
PubMed1998

Inhibition of voltage-gated cationic channels in rat embryonic hypothalamic neurones and C1300 neuroblastoma cells by triphenylethylene antioestrogens.

The effect of the non-steroidal antioestrogens tamoxifen and toremifene on voltage-gated cationic currents was examined in primary cultures of rat hypothalamic neurones and the C1300 mouse neuroblastoma cell line using the whole-cell patch clamp technique. When applied to the external bathing solution both tamoxifen and toremifene were able to inhibit TTX-sensitive sodium currents with IC50 values of 1-2 microM and delayed rectifier type potassium currents (IC50, 2-3 microM). However, only toremifene showed a significant inhibition of the I(A) current (IC50 3 microM). Inhibition of voltage-gated cationic currents was significantly impaired when tamoxifen was applied in a serum-containing solution. The steroidal antioestrogen ICI 182,780 did not inhibit any of the currents at 10 microM.

Animals↗