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PubMed1994

Sodium-selective channels in membranes of rat macrophages.

With the use of the patch-clamp technique, highly selective nonvoltage-gated sodium channels were found in the membrane of rat peritoneal macrophages. The inward single channel currents were measured in cell-attached and outside-out mode experiments at different holding membrane potentials within the range of -60 to +40 mV. The channels had a unitary conductance of 10.2 +/- 0.2 pS with 145 mM Na+ in the external solution at 23-24 degrees C. The results of ion-substitution experiments confirmed that this novel type of cation channel in macrophages is characterized by high selectivity for Na+ over K+ (as for Cs+, NH4+, Ca2+, Ba2+) ions, whose conduction through these sodium-permeable channels was not measurable. Lithium is the only other ion that is transported by this pathway; the unitary conductance was equal to 3.9 +/- 0.2 pS in the Li(+)-containing external solution. Single channel currents and conductance were found to be linearly dependent on the external sodium concentration. Sodium channels in macrophage membrane patches were not blocked by tetrodotoxin (0.01-1 microM). Single sodium currents were reversibly inhibited by the external application of amiloride (0.1-2 mM) and its derivative ethylisopropilamiloride (0.01-0.1 mM). The mechanism of channel block by amiloride and its analogue seems to be different.

Amiloride↗
PubMed1994

Guanine nucleotides modulate steady-state inactivation of voltage-gated sodium channels in frog olfactory receptor neurons.

The voltage for half-inactivation (V1/2) of Na+ currents in frog olfactory receptor neurons (ORNs) under whole-cell voltage clamp showed a shift to more negative potentials with time. Inclusion of guanosine triphosphate (GTP) or its nonhydrolyzable analogue, guanosine-5'-O-3-thiotriphosphate (GTP-gamma-S), which activates G proteins, in the recording pipette, not only gave a more positive V1/2, but also reduced and delayed the negative shift observed in the absence of nucleotides. Guanosine-5'-O-2-thiodiphosphate (GDP-beta-S), a nonhydrolyzable analogue that prevents the binding of GTP to G proteins, did not affect the V1/2 significantly by itself but blocked the positive shift induced by GTP. Since the steady-state activation was not affected, our results indicate that a G protein or a G-protein-dependent process may be important in regulating the steady-state inactivation of Na+ channels in ORNs of the frog.

Animals↗
PubMed1995

Voltage-dependent sodium channels in human small-cell lung cancer cells: role in action potentials and inhibition by Lambert-Eaton syndrome IgG.

Sodium channels of human small-cell lung cancer (SCLC) cells were examined with whole-cell and single-channel patch clamp methods. In the tumor cells from SCLC cell line NCI-H146, the majority of the voltage-gated Na+ channels are only weakly tetrodotoxin (TTX)-sensitive (Kd = 215 nM). With the membrane potential maintained at -60 to -80 mV, these cells produced all-or-nothing action potentials in response to depolarizing current injection (> 20 pA). Similar all-or-nothing spikes were also observed with anodal break excitation. Removal of external Ca2+ did not affect the action potential production, whereas 5 microM TTX or substitution of Na+ with choline abolished it. Action potentials elicited in the Ca(2+)-free condition were reversibly blocked by 4 mM MnCl2 due to the Mn(2+)-induced inhibition of voltage-dependent sodium currents (INa). Therefore, Na+ channels, not Ca2+ channels, underlie the excitability of SCLC cells. Whole-cell INa was maximal with step-depolarizing stimulations to 0 mV, and reversed at +45.2 mV, in accord with the predicted Nernst equilibrium potential for a Na(+)-selective channel. INa evoked by depolarizing test potentials (-60 to +40 mV) exhibited a transient time course and activation/inactivation kinetics typical of neuronal excitable membranes; the plot of the Hodgkin-Huxley parameters, m infinity and h infinity, also revealed biophysical similarity between SCLC and neuronal Na+ channels. The single channel current amplitude, as measured with the inside-out patch configuration, was 1.0 pA at -20 mV with a slope conductance of 12.1 pS. The autoantibodies implicated in the Lambert-Eaton myasthenic syndrome (LES), which are known to inhibit ICa and INa in bovine adrenal chromaffin cells, also significantly inhibited INa in SCLC cells. These results indicate that (i) action potentials in human SCLC cells result from the regenerative increase in voltage-gated Na+ channel conductance; (ii) fundamental characteristics of SCLC Na+ channels are the same as the classical sodium channels found in a variety of excitable cells; and (iii) in some LES patients, SCLC Na+ channels are an additional target of the pathological IgG present in the patients' sera.

Carcinoma, Small Cell↗
PubMed1994

Modification of cloned brain Na+ channels by batrachotoxin.

The effects of batrachotoxin (BTX) on cloned alpha-subunit Na+ channels were examined in CHO-K1 cells (a chinese hamster ovary cell line) transfected with rat brain NaIIA cDNA. Under whole-cell patch clamp conditions, BTX shifted the voltage dependence of the activation process by about 45 mV towards the hyperpolarizing direction and eliminated the inactivating phase of Na+ currents. Repetitive depolarizations greatly facilitated the binding of BTX with NaIIA channels while the membrane was held at -100 mV. In chloramine-T-pretreated cells, the association rate of BTX binding with the NaIIA channel was 6.5-fold faster than that in untreated cells. The estimated association rate constant for BTX binding with the open form of NaIIA channel was 1.11 x 10(6) mol-1.s-1 at room temperature. BTX-modified NaIIA channels were blocked by tetrodotoxin (TTX) in a complicated manner. First, the TTX binding to the closed state of BTX-modified NaIIA channels was not voltage dependent. The KD value of TTX was measured at 8.9 nM, which was similar to that of unmodified channels (KD = 14.2 nM). Second, the block of the open state of BTX-modified NaIIA channels by TTX was voltage dependent; depolarization reduced the potency of TTX block between -20 mV to +50 mV. Below -30 mV, the TTX affinity began to level off, probably because of the increased presence of the closed state. Unexpectedly, steady-state inactivation of BTX-modified NaIIA channels was minimal as measured by the two-pulse protocol, a phenomenon distinctly different from that found in GH3 cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Local anaesthetic-like effect of interleukin-2 on muscular Na+ channels: no evidence for involvement of the IL-2 receptor.

The effects of interleukin-2 (IL-2) on muscular Na+ currents were studied in human myoballs. The transient Na+ inward currents, elicited by repetitive depolarizations at 1 Hz and recorded in the whole-cell mode, were inhibited by the cytokine, the half-maximum effect occurring at about 500 U/ml. The effects resembled those of local anaesthetics without use dependence, as the inactivation (h infinity) curve was shifted in a negative direction while the current/voltage curve was not affected. As with these local anaesthetics, depolarization at 1, 4 and 8 Hz in the presence of IL-2 did not produce any cumulative block. The interaction of IL-2 with the Na+ channels is very fast (within ms) and it is suggested that it occurs when the Na+ channels are in the state of fast inactivation. The recovery from inactivation was only slightly slowed by IL-2, in agreement with the absence of any use dependence. All effects were readily reversible on washout of the cytokine. The effects were seen both in tetrodotoxin-(TTX)-sensitive adult Na+ channels and in TTX-insensitive juvenile channels. In contrast to the whole-cell configuration, no inhibition was visible in the attached-patch configuration. Further, the preincubation with an anti-IL-2-receptor antibody did not prevent the inhibitory effect of IL-2 on the Na+ currents. It is concluded that the cytokine blocks the voltage-dependent muscular Na+ channels by keeping the channels in the state of fast inactivation. An IL-2 receptor and a second messenger system are not likely to be involved in this reaction.

Anesthetics, Local↗
PubMed1995

Phospholipase C activates protein kinase C during induction of slow Na current in Xenopus oocytes.

Protein phosphorylation by protein kinase C (PKC) has recently been shown to be a key event in the induction of the slow inward Na current observed during sustained depolarization of the Xenopus oocyte membrane. The present work investigates the possible pathways leading to PKC activation. PKC is activated by a series of phospholipid metabolites, such as diacylglycerol (DAG) and arachidonic acid produced by phospholipases C (PLC) and A2 (PLA2) respectively. To test whether PKC activation was dependent upon the phospholipid metabolites produced either by PLC or by PLA2, enzyme activity was reduced using selective inhibitors. Results indicated that inhibition of PLA2 activity and inhibition of the enzymes involved in the arachidonic acid cascade failed to affect Na current amplitude. On the other hand, PLC inhibition caused a marked decrease of Na current amplitude. In another series of experiments, Na current was fully restored, in spite of PLC inhibition, by directly enhancing PKC activity with a powerful activator phorbol 12-myristate 13-acetate. These data strongly suggest that PLC is involved in PKC activation during Na channel induction.

Animals↗
PubMed1995

Recombinant interleukin-2 acts like a class I antiarrhythmic drug on human cardiac sodium channels.

Human recombinant interleukin-2 (rIL-2) was bath-applied to isolated human cardiocytes while sodium currents were triggered and registered using the whole-cell recording technique. In the presence of the cytokine the sodium currents were reversibly blocked, 50% peak current reduction occurring at a concentration of 500 U/ml. The current-voltage relationship was not affected, but the steady-state inactivation curve was not affected, but the steady-state inactivation curve was shifted in the negative direction by 15 mV. When 35% of the sodium current was blocked the time constant of recovery from block at -135 mV was in the range of 63 +/- 27 ms. Use dependence was observed only at stimulation frequencies above 4 Hz. Addition of a polyclonal anti-IL-2 antibody to the extracellular solution prevented all of the above effects, while incubation of the cells with a function-blocking monoclonal anti-IL-2 receptor antibody had no influence on the described rIL-2 action. In contrast to rIL-2, recombinant tumor necrosis factor alpha (rTNF-alpha) did not affect the sodium currents. It is concluded that rIL-2 acts like a class I antiarrhythmic drug on human cardiac sodium channels. This might explain some of its proarrhythmic side effects when given intravenously in high doses.

Antibodies↗
PubMed1996

Amiloride-blockable Ca2+-activated Na+-permeant channels in the fetal distal lung epithelium.

The Na+ transport function of alveolar epithelium represents an important mechanism for clearance of fluid in air space at birth. I observed the activity of two types of amiloride-blockable Na+-permeant cation channels in the apical membrane of fetal distal lung epithelium cultured on permeable filters for 2 days after harvesting of the cells from Wistar rats of 20 days gestation (term = 22 days). One type was a nonselective cation (NSC) channel and had a linear current/voltage (I/V) relationship with a single-channel conductance of 26.9 +/- 0.8 pS (n = 5). The other type was highly Na+ selective (i.e. Na+ channel) and had an inwardly rectifying I/V relationship with a single-channel conductance of 11.8 +/- 0.2 pS (n = 5) around resting membrane potential. The NSC channel was more frequently observed (1.37 +/- 0.15 per patch membrane; n = 73) than the Na+ channel (0.15 +/- 0.40 per patch membrane; n = 73). However, the open probability of the NSC channel was smaller than that of the Na+ channel. Both types of the channels were activated by cytosolic Ca2+, however the sensitivity to cytosolic Ca2+ was much higher in the Na+ channel than in the NSC channel. Furthermore, both types of the channels were blocked by amiloride or benzamil. The half-maximal inhibitory concentration (IC50) of amiloride or benzamil of the Na+ channel was 1-2 microM, while that of NSC channel was less than 1 microM. Both channels were activated by insulin.

Amiloride↗
PubMed2003

Isolation and characterization of hainantoxin-IV, a novel antagonist of tetrodotoxin-sensitive sodium channels from the Chinese bird spider Selenocosmia hainana.

A neurotoxin, named hainantoxin-IV, was purified from the venom of the spider Selenocosmia hainana. The amino acid sequence was determined by Edman degradation, revealing it to be a 35-residue polypeptide amidated at its C terminal and including three disulfide bridges: Cys2-Cys17, Cys9-Cys24, and Cys16-Cys31 assigned by partial reduction and sequence analysis. Hainantoxin-IV shares 80% sequence identity with huwentoxin-IV from the spider S. huwena, a potent antagonist that acts at site 1 on tetrodotoxin-sensitive (TTX-S) sodium channels, suggesting that hainantoxin-IV adopts an inhibitor cystine knot structural motif like huwentoin-IV. Under whole-cell voltage-clamp conditions, this toxin has no effect on tetrodotoxin-resistant voltage-gated sodium channels in adult rat dorsal root ganglion neurons, while it blocks TTX-S sodium channels in a manner similar to huwentoxin-IV, and the actions of both toxins on sodium currents are very similar to that of tetrodotoxin. Thus, they define a new family of spider toxins affecting sodium channels.

Amino Acid Sequence↗
PubMed2000

Structure, function and pharmacology of voltage-gated sodium channels.

Voltage-gated sodium channels (VGSCs) are responsible for the initial inwards current during the depolarisation phase of action potential in excitable cells. Therefore, VGSCs are crucial for cardiac and nerve function, since the action potential of nerves and muscle cannot occur without them. Their importance in generation and transmission of signals has been known for more than 40 years but the more recent introduction of new electrophysiological methods and application of molecular biology techniques has led to an explosion of research on many different ion channels, including VGSCs. Their extraordinary biological importance makes them logical and obvious targets for toxins produced by animals and plants for attack or defence. The action of these and similar substances modulating the function of the VGSCs is interesting with respect to their possible use in medicine or use as tools in the study of these molecules. This review summarises recent progress in this research field and, in particular, considers what is known about the relationship of the structure to function, including a current understanding of the pharmacological modulation of VGSCs.

Amino Acid Sequence↗
PubMed2003

Dopaminergic innervation of the rat globus pallidus characterized by microdialysis and immunohistochemistry.

The present study examined the dopaminergic innervation of the rat globus pallidus by in vivo microdialysis and immunohistochemistry in more detail. Using tyrosine hydroxylase immunohistochemistry, two classes of dopaminergic fibers were distinguished morphologically in the globus pallidus. Unilateral infusion of 6-hydroxydopamine into the substantia nigra produced a loss of dopaminergic fiber density in the globus pallidus which was correlated with the nigral extent of the lesion. These findings are in line with the notion that a degenerative loss of nigral dopaminergic cell bodies might also affect the dopamine input of extrastriatal structures such as the globus pallidus. Using in vivo microdialysis, we tested whether dopamine measured in the globus pallidus is of neuronal origin. Perfusion of tetrodotoxin induced a strong and transient decrease of pallidal dopamine. The tetrodotoxin-sensitivity of pallidal dopamine demonstrates the functional significance of the nigropallidal dopaminergic innervation.

Animals↗
PubMed2003

Subthreshold oscillations generated by TTX-sensitive sodium currents in dorsal cochlear nucleus pyramidal cells.

During intracellular recordings in rodent brainstem slice preparations, dorsal cochlear nucleus (DCN) pyramidal cells (PCs) exhibit characteristic discharge patterns to depolarizing current injection that depend on the membrane potential from which the responses are evoked. When depolarized from hyperpolarized potentials, PCs can respond with a short-latency action potential followed by a long silent interval (pauser) or a train of action potentials with a long latency (buildup). During the silent intervals in a pauser or a buildup response, the membrane potential slowly depolarizes towards spike threshold, often exhibiting distinct voltage oscillations of 1-2 mV before the first spike. The subthreshold voltage oscillations were investigated using whole cell recordings from DCN PCs in rat pup (P10-14) brainstem slices. The oscillations were unaffected by excitatory and inhibitory neurotransmitter antagonists, and were not temporally locked to the onset of the depolarization. The oscillations typically became larger as spike threshold was approached, and had a characteristic frequency between 40 and 100 Hz. In the presence of tetrodotoxin (TTX, 500 nM), the oscillations were significantly suppressed, and could not be evoked at any voltage below or above spike threshold. The oscillations were not blocked by phenytoin or Cd2+, but they were affected by prior activity in the neuron for approximately 1 s. We conclude that voltage-gated Na+ channels are required to generate membrane oscillations during the buildup phase. We suggest that the subthreshold oscillations play a role in controlling spike timing in PCs when the membrane potential slowly approaches, or hovers near, spike threshold.

Acoustic Stimulation↗
PubMed2002

Properties of a sodium channel (Na(x)) activated by strong depolarization of Xenopus oocytes.

Short (<1 sec) duration depolarization of Xenopus laevis oocytes to voltages greater than +40 mV activates a sodium-selective channel (Na(x)) with sodium permeability five to six times greater than the permeability of other monovalent cations examined, including K+, Rb+, Cs+, TMA+, and Choline+. The permeability to Li+ is about equal to that of Na+. This channel was present in all oocytes examined. The kinetics, voltage dependence and pharmacology of Na(x)distinguish it from TTX-sensitive or epithelial sodium channels. It is also different from the sodium channel of Xenopus oocytes activated by prolonged depolarization, which is more highly selective for Na+, requires prolonged depolarization to be activated, and is blocked by Li+. Intracellular Mg2+ reversibly inhibits Na(x), whereas extracellular Mg2+ does not have an inhibitory effect. Intracellular Mg2+ inhibition of Na(x), is voltage dependent, suggesting that Mg2+ binding occurs within the membrane field. Eosin is also a reversible voltage-dependent intracellular inhibitor of Na(x), suggesting that a P-type ATPase may mediate the current. An additional cytoplasmic factor is involved in maintaining Na(x) since the current runs down in internally perfused oocytes and excised membrane patches. The rundown is reversible by reintroduction of the membrane patch into oocyte cytoplasm. The cytoplasmic factor is not ATP, because ATP has no effect on Na(x) current magnitude in either cut-open or inside-out patch preparations. Extracellular Gd3+ is also an inhibitor of Na(x). Na(x) activation follows a sigmoid time course. Its half-maximal activation potential is +100 mV and the effective valence estimated from the steepness of conductance activation is 1.0. Na(x) deactivates monoexponentially upon return to the holding potential (-40 mV). The deactivation rate is voltage dependent, increasing at more negative membrane potentials.

Amiloride↗
PubMed2005

State-dependent block of human cardiac hNav1.5 sodium channels by propafenone.

State-dependent blockade of human cardiac hNav1.5 sodium channels by propafenone was studied using whole-cell patch clamp techniques. Both a direct investigation using cells with inactivation-deficient sodium channels and an algorithmic approach used on cells with wild-type channels revealed a rapid binding of propafenone to the open state. This occurs approximately 4000 and 700 times faster than the binding to the resting and inactivated state, respectively. An established mathematical "gating" model was modified to represent the experimental data.

Anti-Arrhythmia Agents↗
PubMed2000

Involvement of protein tyrosine kinase in osmoregulation of Na(+) transport and membrane capacitance in renal A6 cells.

Renal A6 cells have been reported in which hyposmolality stimulates Na(+) transport by increasing the number of conducting amiloride-sensitive 4-pS Na(+) channels at the apical membrane. To study a possible role of protein tyrosine kinase (PTK) in the hyposmolality-induced signaling, we investigated effects of PTK inhibitors on the hyposmolality-induced Na(+) transport in A6 cells. Tyrphostin A23 (a PTK inhibitor) blocked the stimulatory action of hyposmolality on a number of the conducting Na(+) channels. Tyrphostin A23 also abolished macroscopic Na(+) currents (amiloride-sensitive short-circuit current, I(Na)) by decreasing the elevating rate of the hyposmolality-increased I(Na). Genistein (another type of PTK inhibitor) also showed an effect similar to tyrphostin A23. Brefeldin A (BFA), which is an inhibitor of intracellular translocation of protein, blocked the action of hyposmolality on I(Na) by diminishing the elevating rate of the hyposmolality-increased I(Na), mimicking the inhibitory action of PTK inhibitor. Further, hyposmolality increased the activity of PTK. These observations suggest that hyposmolality would stimulate Na(+) transport by translocating the Na(+) channel protein (or regulatory protein) to the apical membrane via a PTK-dependent pathway. Further, hyposmolality also caused an increase in the plasma (apical) membrane capacitance, which was remarkably blocked by treatment with tyrphostin A23 or BFA. These observations also suggest that a PTK-dependent pathway would be involved in the hyposmolality-stimulated membrane fusion in A6 cells.

Animals↗
PubMed1997

Competition for binding between veratridine and KIFMK: an open channel blocking peptide of the RIIA sodium channel.

Veratridine, an alkaloid isolated from the rhizome of V. album, binds and slows the inactivation of the brain sodium channels. The synthetic pentapeptide KIFMK causes a voltage- and use-dependent open-channel block of the RIIA (rat brain type IIA) sodium channel (Eaholtz, Scheuer & Catterall, 1994). Our studies on the RIIA sodium channel expressed in CHO cells reveal that the fraction of veratridine modified sodium channels decreases linearly with increasing KIFMK concentration. However, the time constant for dissociation of veratridine from the channel remains unchanged in the presence of a high concentration of KIFMK, as opposed to that in the presence of QX314 where the dissociation appears to be more complex. These data are consistent with mutually exclusive binding of the open channel blocking peptide and veratridine to the brain sodium channel.

Animals↗
PubMed2004

Voltage-gated Na+ channels: multiplicity of expression, plasticity, functional implications and pathophysiological aspects.

Voltage-gated Na+ channels (VGSCs) are well known for mediating regenerative cell membrane depolarization and conduction of electrical signalling in nerves and muscles. However, VGSCs may also be expressed in traditionally "non-excitable" cell types, including lymphocytes, glia, fibroblasts and metastatic cancer cells of epithelial origin. Both the diversity and modulation of VGSC expression are far more complex than was initially apparent. There are at least 10 different genes that encode the alpha-subunits of VGSCs. Since VGSCs can contribute to a range of human disease conditions, it is important to understand both the control and consequences of VGSC functioning and how these aspects may be altered under pathophysiological conditions. Such mechanisms can be at the transcriptional, pre-translational or post-translational levels. This article reviews recent literature that has contributed to our understanding of how individual VGSC subtypes can generate their unique physiological signatures within different cell types. We also highlight emerging areas of interest, in particular, the finding of multiple expression of individual VGSC subtypes within single cells, the generation of alternative splice variants and the increasingly complex set of mechanisms of plasticity through which individual VGSC subtypes may be subtly controlled, including intracellular trafficking of VGSC protein.

Carcinoma↗