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PubMed2006

PACAP support of neuronal survival requires MAPK- and activity-generated signals.

Pituitary adenylate cyclase-activating polypeptide (PACAP) is expressed in the parasympathetic ciliary ganglion (CG) and modulates nicotinic acetylcholine receptor function. PACAP also provides trophic support, promoting partial survival of CG neurons in culture and full survival when accompanied by membrane depolarization. We probed the adenylate cyclase (AC) and phospholipase-C (PLC) transduction cascades stimulated by PACAP to determine their respective roles in supporting neuronal survival and examined their interaction with signals generated by membrane activity. While PLC-dependent signaling was dispensable, AC-generated signals proved critical for PACAP to support neuronal survival. Specifically, PACAP-supported survival was mimicked by 8Br-cAMP and blocked by inhibiting either PKA or the phosphorylation of mitogen-activated protein kinase (MAPK). The ability of PACAP to promote survival was additionally dependent on spontaneous activity as blocking Na+ or Ca2+ channel currents completely abrogated trophic effects. Our results underscore the importance of coordinated MAPK- and activity-generated signals in transducing neuropeptide-mediated parasympathetic neuronal survival.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed2006

Analysis of the variation in use-dependent inactivation of high-threshold tetrodotoxin-resistant sodium currents recorded from rat sensory neurons.

This study addressed variation in the use-dependent inactivation (UDI) of high-threshold tetrodotoxin-resistant Na+ currents (TTX-R currents) and action potential firing behavior among acutely isolated rat dorsal root ganglion (DRG) cells. UDI was quantified as the percent decrease in current amplitude caused by increasing the current activation rate from 0.1-1.0 Hz for 20 s. TTX-R current UDI varied from 6% to 66% among 122 DRG cells examined, suggesting the existence of two or more levels of UDI. The voltage-dependency of the TTX-R currents was consistent with Na(V)1.8, regardless of UDI. However, TTX-R currents with more UDI had a more negative voltage-dependency of inactivation, a greater tendency to enter slow inactivation, and a slower recovery rate from slow inactivation, compared with those with less UDI. TTX-R currents with more UDI ran down faster than those with less UDI. However, UDI itself changed little over time, regardless of the initial UDI level observed in a particular DRG cell. Together, these two observations suggest that individual DRG cells did not express mixtures of TTX-R channels that varied regarding UDI. TTX-R current UDI was correlated with expression of a low-threshold A-current and whole-cell capacitance, suggesting that it varied among different nociceptor types. Whole-cell inward currents (WCI-currents), recorded without channel blockers, also exhibited UDI. WCI-current UDI varied similarly to TTX-R current UDI in magnitude, and relative to whole-cell capacitance and A-current expression, suggesting that the WCI-currents were carried predominantly by TTX-R channels. DRG cells with more WCI-current UDI exhibited a greater decrease in action potential amplitude and number, and a greater increase in action potential threshold over seven ramp depolarizations, compared with DRG cells with less WCI-current UDI. Variation in UDI of Na(V)1.8 channels expressed by different nociceptor types could contribute to shaping their individual firing patterns in response to noxious stimuli.

Action Potentials↗
PubMed1997

Blocking mechanisms of ketamine and its enantiomers in enzymatically demyelinated peripheral nerve as revealed by single-channel experiments.

BACKGROUND: Ketamine shows, besides its general anesthetic effect, a local anesthetic-like action that is due to blocking of peripheral nerve sodium currents. In this study, the stereoselectivity of the blocking effects of the ketamine enantiomers S(+) and R(-) was investigated in sodium and potassium channels in peripheral nerve membranes. METHODS: Ion channel blockade of ketamine was investigated in enzymatically dissociated Xenopus sciatic nerves in multiple-channel and in single-channel outside-out patches. RESULTS: Concentration-effect curves for the Na+ peak current revealed half-maximal inhibiting concentrations (IC50) of 347 microM and 291 microM for S(+) and R(-) ketamine, respectively. The potential-dependent K+ current was less sensitive than the Na+ current with IC50 values of 982 microM and 942 microM. The most sensitive ion channel was the flickering background K+ channel, with IC50 values of 168 microM and 146 microM for S(+) and R(-) ketamine. Competition experiments suggest one binding site at the flicker K+ channel, with specific binding affinities for each of the enantiomers. For the Na+ channel, the block was weaker in acidic (pH = 6.6) than in neutral (pH = 7.4) and basic (pH = 8.2) solutions; for the flicker K+ channel, the block was weaker in acidic and stronger in basic solutions. CONCLUSIONS: Ketamine blockade of sodium and potassium channels in peripheral nerve membranes shows no stereoselectivity except for the flicker K+ channel, which showed a very weak stereoselectivity in favor of the R(-) form. This potential-insensitive flicker K+ channel may contribute to the resting potential. Block of this channel and subsequent depolarization of the resting membrane potential leads, besides to direct Na+ channel block, to inexcitability via Na+ channel inactivation.

Anesthetics, Dissociative↗
PubMed2000

Inhibition of different pathways influencing Na(+) homeostasis protects organotypic hippocampal slice cultures from hypoxic/hypoglycemic injury.

A prominent feature of cerebral ischemia is the excessive intracellular accumulation of both Na(+) and Ca(2+), which results in subsequent cell death. A large number of studies have focused on pathways involved in the increase of the intracellular Ca(2+) concentration [Ca(2+)](i), whereas the elevation of intracellular Na(+) has received less attention. In the present study we investigated the effects of inhibitors of different Na(+) channels and of the Na(+)/Ca(2+) exchanger, which couples the Na(+) to the Ca(2+) gradient, on ischemic damage in organotypic hippocampal slice cultures. The synaptically evoked population spike in the CA1 region was taken as a functional measure of neuronal integrity. Neuronal cell death was assessed by propidium iodide staining. The Na(+) channel blocker tetrodotoxin, and the NMDA receptor blocker MK 801, but not the AMPA/kainate receptor blocker NBQX prevented ischemic cell death. The novel Na(+)/Ca(2+) exchange inhibitor 2-[2-[4-(4-nitrobenzyloxy)phenyl]ethyl]isothiourea methanesulfonate (KB-R7943), which preferentially acts on the reverse mode of the exchanger, leading to Ca(2+) accumulation, also reduced neuronal damage. At higher concentrations, KB-R7943 also inhibits Ca(2+) extrusion by the forward mode of the exchanger and exaggerates neuronal cell death. Neuroprotection by KB-R7943 may be due to reducing the [Ca(2+)](i) increase caused by the exchanger.

Animals↗
PubMed1997

A possible role of the redox interactions in the dual, activatory and inhibitory, action of DPI 201-106 on the potential-dependent Na+ channels.

Dual, activatory and inhibitory, effects of a cardiotonic drug DPI 201-106 on Na+ channels were compared with the redox properties of the DPI itself and of the constituents of its molecule, indole and piperazine. The indole component accepted electrons from radical intermediates of the light excited dye; the piperazine part of DPI acted as an electron donor in the same radical reactions. These data extend the previously obtained results which characterized organic blockers of Na+ and Ca2+ channels as electron donors, whereas activators of these channels were shown to be electron acceptors in test radical reactions. The whole DPI 201-106 molecule revealed both the electron-donor and electron-acceptor activity. The described electrophysiological effects of this compound (G. Wang et al., 1989) are discussed within the framework of the Na+ channel redox model (B. Marinov, 1991).

Allosteric Regulation↗
PubMed2005

Inhibition of Na+ channel currents in rat myoblasts by 4-aminopyridine.

Our previous study revealed that 4-aminopyridine (4-AP), a specific blocker of A-type current, could also inhibit inward Na+ currents (I(Na)) with a state-independent mechanism in rat cerebellar granule cells. In the present study, we report an inhibitory effect of 4-AP on voltage-gated and tetrodotoxin (TTX)-sensitive I(Na) recorded from cultured rat myoblasts. 4-AP inhibited I(Na) amplitude in a dose-dependent manner between the concentrations of 0.5 and 10 mM without significant alteration in the activation or inactivation kinetics of the channel. By comparison to the 4-AP-induced inhibitory effect on cerebellum neurons, the inhibitory effect on myoblasts was enhanced through repetitive pulse and inflected by changing frequency. Specifically, the lower the frequency of pulse, the higher the inhibition observed, suggesting that block manner is inversely use-dependent. Moreover, experiments adding 4-AP to the intracellular solution indicate that the inhibitory effects are localized inside the cell. Additionally, 4-AP significantly modifies the properties of steady-state activation and inactivation kinetics of the channel. Our data suggest that the K+ channel blocker 4-AP inhibits both neuron and myoblast Na+ channels via different mechanisms. These findings may also provide information regarding 4-AP-induced pharmacological and toxicological effects in clinical use and experimental research.

4-Aminopyridine↗
PubMed2000

Selective block of late currents in the DeltaKPQ Na(+) channel mutant by pilsicainide and lidocaine with distinct mechanisms.

The congenital long QT syndrome is an inherited disorder characterized by a delay in cardiac repolarization, leading to lethal cardiac arrhythmias such as torsade de pointes. One form of this disease involves mutations in the voltage-dependent cardiac Na(+) channel, which includes an in-frame deletion of three amino acids (Lys-1505, Pro-1506, and Gln-1507; DeltaKPQ). The potential for selective suppression of the mutant was examined by heterologous expression of DeltaKPQ-Na(+) channels in Chinese hamster fibroblast cells via single-channel recording. In a single-channel cell-attached patch study, DeltaKPQ-Na(+) channels yielded currents that peaked at approximately 1 ms after voltage steps to 0 mV with aberrant late currents, which were composed of burst and isolated openings. The affinity of certain anesthetics (pilsicainide and lidocaine) to the late currents of the mutant channels was examined. It was revealed that 1) pilsicainide (1 microM), an open channel blocker of voltage-dependent Na(+) channels, remarkably decreased the late currents primarily by the shortening of burst duration without suppressing the initial peak current; and 2) lidocaine (1 microM), an inactivated channel blocker, decreased the late currents primarily by the suppression of isolated channel openings. Because the late currents in DeltaKPQ mutants are mainly composed of the burst openings, we conclude that pilsicainide is capable of selectively blocking the late currents in the mutant Na(+) channels that show dominant abnormal burst openings such as in DeltaKPQ mutants.

Animals↗
PubMed1997

Steroid hormone-dependent expression of blocker-sensitive ENaCs in apical membranes of A6 epithelia.

Weak channel blocker-induced noise analysis was used to determine the way in which the steroids aldosterone and corticosterone stimulated apical membrane Na+ entry into the cells of tissue-cultured A6 epithelia. Among groups of tissues grown on a variety of substrates, in a variety of growth media, and with cells at passages 73-112, the steroids stimulated both amiloride-sensitive and amiloride-insensitive Na+ transport as measured by short-circuit currents in chambers perfused with either growth medium or a Ringer solution. From baseline rates of blocker-sensitive short-circuit current between 2 and 7 microA/cm2, transport was stimulated about threefold in all groups of experiments. Single channel currents averaged near 0.3 pA (growth medium) and 0.5 pA (Ringer) and were decreased 6-20% from controls by steroid due to the expected decreases of fractional transcellular resistance. Irrespective of baseline transport rates, the steroids in all groups of tissues stimulated transport by increase of the density of blocker-sensitive epithelial Na+ channels (ENaCs). Channel open probability was the same in control and stimulated tissues, averaging approximately 0.3 in all groups of tissues. Accordingly, steroid-mediated increases of open channel density responsible for stimulation of Na+ transport are due to increases of the apical membrane pool of functional channels and not their open probability.

Aldosterone↗
PubMed2001

Voltage-dependent inhibition of brain Na(+) channels by American ginseng.

American ginseng (Panax quinquefolius) is a major species of ginseng that has many pharmacological effects. Studies have demonstrated that constituents of ginseng have neuroprotective effects during ischemia. Neuronal damage during ischemic episodes has been associated with abnormal Na(+) fluxes. Drugs that block voltage-dependent Na(+) channels provide cytoprotection during cerebral ischemia. We thus hypothesized that American ginseng may block Na(+) channels. In this study, effects of an American ginseng aqueous extract was evaluated in tsA201 cells transfected with cDNA expressing alpha subunits of the Brain(2a) Na(+) channel using the whole-cell patch clamp technique. We found that American ginseng extract tonically and reversibly blocked the channel in a concentration- and voltage-dependent manner. It shifted the voltage-dependence of inactivation by 14 mV (3 mg/ml) in the hyperpolarizing direction and delayed recovery from inactivation, whereas activation of the channel was unaffected. Ginsenoside Rb(1), a major constituent of the American ginseng extract, produced similar effects. The data were compared with the actions of lidocaine, a Na(+) channel blocker. Our results suggest that Na(+) channel block by American ginseng extract and Rb(1) was primarily due to interaction with the inactive state of the channel. Inhibition of the Na(+) channel activity by American ginseng extract may contribute to its neuroprotective effect during ischemia.

Brain↗
PubMed2004

Stretch-activated channels in stretch-induced muscle damage: role in muscular dystrophy.

1. Stretch-induced muscle injury results in the damage that causes reduced force and increased membrane permeability. This muscle damage is caused, in part, by ionic entry through stretch-activated channels and blocking these channels with Gd3+ or streptomycin reduces the force deficit associated with damage. 2. Dystrophin-deficient muscles are more susceptible to stretch-induced muscle injury and the recovery from injury can be incomplete. We have found that Na+ entry associated with stretch-induced injury is enhanced in dystrophin-deficient muscles and that blockers of stretch-activated channels are capable of preventing ionic entry and reducing muscle damage. 3. A model is presented that proposes links between stretch-induced injury, opening of stretch-activated channels, increased levels of intracellular ions and various forms of muscle damage. Although changes in Na+ accompany stretch-induced muscle injury, we believe that changes in Ca2+ probably have a more central role in the damage process.

Animals↗
PubMed1996

Inhibition of amiloride-sensitive Na+ channel by isothiouronium derivatives.

The effects on the amiloride-blockable Na+ channel of a family of recently synthesized isothiouronium derivatives were measured in plasma membrane vesicles from rat distal colon. Some of these derivatives act as high-affinity Na(+)-like antagonists on the Na(+)-K(+)-adenosinetriphosphatase. One of the reagents tested, 1-bromo-2,4,6-tris(isothiouronium methyl)-benzene tribromide (Br-TITU), was found to be a potent blocker of the Na+ channel. At neutral pH, Br-TITU rapidly inhibits the channel mediated 22Na+ uptake, with an inhibition constant of 94 +/- 39 nM. The inhibition observed is specific and reversible. 1,3-Dibromo-2,4,6-tris(isothiouronium methyl)benzene tribromide and Br-TITU derivatives with methyl and phenyl substitutions on the isothiouronium moiety were much less effective blockers. Incubation of cells with Br-TITU at alkaline (but not neutral) pH produces irreversible inactivation of channels, possibly due ot covalent modification of a lysine residue. This inactivation can be attenuated by amiloride but not by Na+. Thus Br-TITU may be a useful reagent in identifying essential residues of the channel protein.

Amiloride↗
PubMed2005

Proximal persistent Na+ channels drive spike afterdepolarizations and associated bursting in adult CA1 pyramidal cells.

In many principal brain neurons, the fast, all-or-none Na+ spike initiated at the proximal axon is followed by a slow, graded after depolarization (ADP). The spike ADP is critically important in determining the firing mode of many neurons; large ADPs cause neurons to fire bursts of spikes rather than solitary spikes. Nonetheless, not much is known about how and where spike ADPs are initiated. We addressed these questions in adult CA1 pyramidal cells, which manifest conspicuous somatic spike ADPs and an associated propensity for bursting, using sharp and patch microelectrode recordings in acutely isolated hippocampal slices and single neurons. Voltage-clamp commands mimicking spike waveforms evoked transient Na+ spike currents that declined quickly after the spike but were followed by substantial sustained Na+ spike after currents. Drugs that blocked the persistent Na+ current (INaP), markedly suppressed the sustained Na+ spike after currents, as well as spike ADPs and associated bursting. Ca2+ spike after currents were much smaller, and reducing them had no noticeable effect on the spike ADPs. Truncating the apical dendrites affected neither spike ADPs nor the firing modes of these neurons. Application of INaP blockers to truncated neurons, or their focal application to the somatic region of intact neurons, suppressed spike ADPs and associated bursting, whereas their focal application to distal dendrites did not. We conclude that the somatic spike ADPs are generated predominantly by persistent Na+ channels located at or near the soma. Through this action, proximal INaP critically determines the firing mode and spike output of adult CA1 pyramidal cells.

Action Potentials↗
PubMed2000

Role of voltage-gated Na+ channels in hypoxia-induced neuronal injuries.

1. Mammalian neurons in the central nervous system are vulnerable to oxygen deprivation. In clinical conditions, such as stroke or apnoea, permanent loss of neuronal functions can occur within minutes of severe hypoxia. 2. Recent studies have focused on the role of Na+ in acute neuronal responses to hypoxia. These studies have shown that the influx of extracellular Na+ is an important factor in hypoxia-induced injury and that blockade of voltage-gated Na+ channels reduces hypoxic responses and injury of neurons. Yet, the mechanism underlying the effect of blockade of Na+ channels on hypoxic injury is unclear. 3. The aim of the present review is to discuss the above topics given the current understanding of the role of Na+ channels in hypoxia and its implications on therapeutic strategy for preventing hypoxia-induced neurological damage. 4. It has been known that the maintenance of ionic homeostasis and membrane properties in neurons are improved by reducing the activity of voltaged-gated Na+ channels during acute hypoxia. 5. Recent studies suggest that persistent Na+ current and Na+-dependent exchangers may play a role in Na+ influx and neuronal injury during hypoxia. 6. The neuroprotective action of blockers of the Na+ channel may also be via the improved maintainance of intracellular energy levels because the action is dependent on cellular energy levels and extracellular glucose during hypoxia. 7. Hence, the blockade of voltage-gated Na+ channels reduces the excitability of neurons, Na+ influx and the accumulation of intracellular Na+. These improve the ionic homeostasis and cellular energy levels and, thus, prevent hypoxia-induced neuronal injury and neuronal damage mediated by Ca2+ overload.

Animals↗
PubMedDate not supplied

[Membrane mechanisms of effects of antihypoxic agents bemethyl and almide on neurons of Mollusca].

Membranotropic effects of the antihypoxants bemithyl and almide, structural analogs of thiobenzimidazole, have been studied on the isolated neuronal preparations of Lymaea stagnalis branchycephalic mollusk. Both drugs in a concentration range of 100-1000 microM produced a reversible, dose-dependent nonselective single-phase blocking action upon the ion channels and completely blocked the channels at a concentration of 10 mM. Therefore, bemithyl and almide are active membranotropic compounds capable (in sufficiently high concentrations) of changing the conductivity of slow sodium, calcium, and potassium ion channels in excitable cells. The protective antihypoxant drug reactions on a systemic level of the organism are probably related to the fact that both drugs in small concentrations are capable of hyperpolarizing the cell membrane, activating the ion channel function, and stabilizing the action potential under hypoxia conditions; in greater concentrations, bemithyl and almide are capable of blocking ion currents, thus reducing the excitability of cells and protecting them from overstress.

Allyl Compounds↗
PubMed2002

Inhibition of Na(+) current by imipramine and related compounds: different binding kinetics as an inactivation stabilizer and as an open channel blocker.

Use-dependent block of Na(+) channels plays an important role in the action of many medications, including the anticonvulsants phenytoin, carbamazepine, and lamotrigine. These anticonvulsants all slowly yet selectively bind to a common receptor site in inactivated but not resting Na(+) channels, constituting the molecular basis of the use-dependent block. However, it remains unclear what channel gating process "makes" the receptor, where the receptor is located, and how the slow drug binding rate (to the inactivated channels) is contrived. Imipramine has a diphenyl structural motif almost identical to that in carbamazepine (a dibenzazepine tricyclic compound), as well as a tertiary amine chain similar to that in many prototypical local anesthetics, and has also been reported to inhibit Na(+) channels in a use-dependent fashion. We found that imipramine selectively binds to the inactivated (dissociation constant approximately 1.3 microM) rather than the resting Na(+) channels (dissociation constant >130 microM). Moreover, imipramine rapidly blocks open Na(+) channels, with a binding rate approximately 70-fold faster than its binding to the inactivated channels. Similarly, carbamazepine and diphenhydramine are open Na(+) channel blockers with faster binding rates to the open than to the inactivated channels. These findings indicate that the anticonvulsant receptor responsible for the use-dependent block of Na(+) channels is located in or near the pore (most likely in the pore mouth) and is made suitable for drug binding during channel activation. The receptor, however, continually changes its conformation in the subsequent gating process, causing the slower drug binding rates to the inactivated Na(+) channels.

Adrenergic Uptake Inhibitors↗
PubMed2003

[Cerebral ischemia-hypoxia and biophysical mechanisms of neurodegeneration and neuroprotection effects].

Neuronal responses to hypoxia-ischemia can be acute or chronic. In the early stages neuronal responses to ischemia-hypoxia are dependent on the modulation of ion channels. Acute responses relay mainly on O2-regulated ion channels which mediate adaptive changes in neuron excitability. Energy failure, an early consequence of hypoxia-ischemia, causes disruption of ionic homeostasis and accumulation of extracellular neurotransmitters. NMDA and AMPA/kainate receptors and Ca2+ channels contribute to excitotoxic neuronal degeneration. Excitotoxicity leads to increased Ca2+ influx, which can activate cytotoxic intracellular pathways. Reactive oxygen species (oxygen free radicals) generated during ischemia-reperfusion contribute to the injury. Oxygen free-radicals serve as important signalling molecules that trigger inflammation and apoptosis. Excitatory amino acid-receptor antagonists and Ca2+ channels blockers can provide neuroprotection in experimental models of hypoxia-ischemia but disrupt normal brain function. Because of their relative lack of behavioral side-effects, voltage-dependent Na+ channels blockers may have advantage over other neuroprotective mechanisms. The blockade of voltage-gated Na+ channels reduces the excitability of neurons, Na+ influx and the accumulation of intracellular Na+. These improve the ionic homeostasis and cellular energy levels and prevent ischemia-hypoxia induced neuronal injury and neuronal damage mediated by Ca2+ overload.

Animals↗
PubMed2002

Differential effects of remacemide and desglycinyl-remacemide on epileptiform burst firing in the rat hippocampal slice.

Remacemide is a potential anticonvulsant drug with an active metabolite, desglycinyl-remacemide (DGR). Both moieties have been reported to block neuronal Na(+) channels and the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor. The effects of remacemide and DGR on zero Mg(2+)/4-aminopyridine-induced epileptiform discharges were investigated in the rat hippocampal slice preparation and compared with carbamazepine (CBZ), a prototypic Na(+) channel blocker, and AR-R15896AR, a putative NMDA channel blocker. Remacemide (0-100 microM) was without significant effect, while DGR, CBZ and AR-R15896AR all decreased burst frequency in a concentration (0-100 microM) dependent manner. These findings suggest that remacemide is not sufficiently potent at the Na(+) channel or NMDA receptor to attenuate epileptiform activity in this model and that the anticonvulsant effects of the drug may be mediated by DGR.

4-Aminopyridine↗
PubMed2005

Electrophysiologically identified subpopulations of taste bud cells.

The heterogeneous population of mammalian taste cells includes several cellular subtypes specializing in distinct physiological functions. They are poorly understood at the single cell level because the available physiological data have generally been obtained from unidentified taste cells. We recorded them from individual taste cells isolated from circumvallate, foliate, and fungiform papilla of the mouse, employing the patch clamp technique, and tried to elucidate whether universal electrophysiological criteria may be established for the identification of functionally different cellular subpopulations. It was found that irrespective of the papillae type, most ( approximately 96%) of robust taste cells could be categorized into three distinct subgroups on the basis of families of whole-cell (WC) currents exhibited in response to membrane polarization. The validity of this quite simple criterion was further confirmed by using different voltage clamp protocols, ion substitutions, and channel blockers to record different ionic currents, including voltage-gated (VG) Ca(2+), inward-rectifying K(+), and hyperpolarization-activated currents. Given that our findings are based on the statistically significant number of recordings, we believe that the electrophysiological identification of taste cells presented here may be effective for further studies on single taste cell physiology, including taste transduction.

Algorithms↗