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Voltage-dependent Sodium Channels (voltage-dependent + sodium_channel)
Selected AbstractsExpression of Nav1.6 sodium channels by Schwann cells at neuromuscular junctions: Role in the motor endplate disease phenotypeGLIA, Issue 1 2006Magali Musarella Abstract In addition to their role in action potential generation and fast synaptic transmission in neurons, voltage-dependent sodium channels can also be active in glia. Terminal Schwann cells (TSCs) wrap around the nerve terminal arborization at the neuromuscular junction, which they contribute to shape during development and in the postdenervation processes. Using fluorescent in situ hybridization (FISH), immunofluorescence, and confocal microscopy, we detected the neuronal Nav1.6 sodium channel transcripts and proteins in TSCs in normal adult rats and mice. Nav1.6 protein co-localized with the Schwann cell marker S-100 but was not detected in the SV2-positive nerve terminals. The med phenotype in mice is due to a mutation in the SCN8A gene resulting in loss of Nav1.6 expression. It leads to early onset in postnatal life of defects in neuromuscular transmission with minimal alteration of axonal conduction. Strikingly, in mutant mice, the nonmyelinated pre-terminal region of axons showed abundant sprouting at neuromuscular junctions, and most of the ,-bungarotoxin-labeled endplates were devoid of S-100- or GFAP-positive TSCs. Using specific antibodies against the Nav1.2 and Nav1.6 sodium channels, ankyrin G and Caspr 1, and a pan sodium channel antibody, we found that a similar proportion of ankyrin G-positive nodes of Ranvier express sodium channels in mutant and wild-type animals and that nodal expression of Nav1.2 persists in med mice. Our data supports the hypothesis that the lack of expression of Nav1.6 in Schwann cells at neuromuscular junctions might play a role in the med phenotype. © 2005 Wiley-Liss, Inc. © 2005 Wiley-Liss, Inc. [source] Modulation of calcium entry and glutamate release in cultured cerebellar granule cells by palytoxinJOURNAL OF NEUROSCIENCE RESEARCH, Issue 8 2006Carmen Vale Abstract A channel open on the membrane can be formed by palytoxin (PTX). Ten nanomolar PTX caused an irreversible increase in the cytosolic calcium concentration ([Ca2+]c), which was abolished in the absence of external calcium. The increase was eliminated by saxitoxin (STX) and nifedipine (NIF). Calcium rise is secondary to the membrane depolarization. PTX effect on calcium was dependent on extracellular Na+. Li+ decreased the PTX-evoked rise in [Ca2+]c; replacement of Na+ by N-methyl-D-glucamine (NMDG) abolished PTX-induced calcium increase. [Ca2+]c increase by PTX was strongly reduced after inhibition of the reverse operation of the Na+/Ca2+ exchanger, in the presence of antagonists of excitatory amino acid (EAA) receptors, and by inhibition of neurotransmitter release. PTX did not modify calcium extrusion by the plasma membrane Ca2+ -ATPase (PMCA), because blockade of the calcium pump increased rather than decreased the PTX-induced calcium influx. Extracellular levels of glutamate and aspartate were measured by HPLC and exocytotic neurotransmitter release by determination of synaptic vesicle exocytosis using total internal reflection fluorescence microscopy (TIRFM). PTX caused a concentration-dependent increase in EAA release to the culture medium. Ten nanomolar PTX decreased cell viability by 30% within 5 min. PTX-induced calcium influx involves three pathways: Na+ -dependent activation of voltage-dependent sodium channels (VDSC) and voltage-dependent calcium channels (VDCC), reverse operation of the Na+/Ca2+ exchanger, and indirect activation of EAA receptors through glutamate release. The neuronal injury produced by the toxin could be partially mediated by the PTX-induced overactivation of EAA receptors, VDSC, VDCC and the glutamate efflux into the extracellular space. © 2006 Wiley-Liss, Inc. [source] After-effects of near-threshold stimulation in single human motor axonsTHE JOURNAL OF PHYSIOLOGY, Issue 3 2005Hugh Bostock Subthreshold electrical stimuli can generate a long-lasting increase in axonal excitability, superficially resembling the phase of superexcitability that follows a conditioning nerve impulse. This phenomenon of ,subthreshold superexcitability' has been investigated in single motor axons in six healthy human subjects, by tracking the excitability changes produced by conditioning stimuli of different amplitudes and waveforms. Near-threshold 1 ms stimuli caused a mean decrease in threshold at 5 ms of 22.1 ± 6.0% (mean ±s.d.) if excitation occurred, or 6.9 ± 2.6% if excitation did not occur. The subthreshold superexcitability was maximal at an interval of about 5 ms, and fell to zero at 30 ms. It appeared to be made up of two components: a passive component linearly related to conditioning stimulus amplitude, and a non-linear active component. The active component appeared when conditioning stimuli exceeded 60% of threshold, and accounted for a maximal threshold decrease of 2.6 ± 1.3%. The passive component was directly proportional to stimulus charge, when conditioning stimulus duration was varied between 0.2 and 2 ms, and could be eliminated by using triphasic stimuli with zero net charge. This change in stimulus waveform had little effect on the active component of subthreshold superexcitability or on the ,suprathreshold superexcitability' that followed excitation. It is concluded that subthreshold superexcitability in human motor axons is mainly due to the passive electrotonic effects of the stimulating current, but this is supplemented by an active component (about 12% of suprathreshold superexcitability), due to a local response of voltage-dependent sodium channels. [source] Short- and long-term differential effects of neuroprotective drug NS-7 on voltage-dependent sodium channels in adrenal chromaffin cellsBRITISH JOURNAL OF PHARMACOLOGY, Issue 4 2000Hiroki Yokoo In cultured bovine adrenal chromaffin cells, NS-7 [4-(4-fluorophenyl)-2-methyl-6-(5-piperidinopentyloxy) pyrimidine hydrochloride], a newly-synthesized neuroprotective drug, inhibited veratridine-induced 22Na+ influx via voltage-dependent Na+ channels (IC50=11.4 ,M). The inhibition by NS-7 occurred in the presence of ouabain, an inhibitor of Na+,K+ ATPase, but disappeared at higher concentration of veratridine, and upon the washout of NS-7. NS-7 attenuated veratridine-induced 45Ca2+ influx via voltage-dependent Ca2+ channels (IC50=20.0 ,M) and catecholamine secretion (IC50=25.8 ,M). Chronic (12 h) treatment of cells with NS-7 increased cell surface [3H]-STX binding by 86% (EC50=10.5 ,M; t1/2=27 h), but did not alter the KD value; it was prevented by cycloheximide, an inhibitor of protein synthesis, or brefeldin A, an inhibitor of vesicular transport from the trans -Golgi network, but was not associated with increased levels of Na+ channel ,- and ,1 -subunit mRNAs. In cells subjected to chronic NS-7 treatment, 22Na+ influx caused by veratridine (site 2 toxin), ,-scorpion venom (site 3 toxin) or ,-scorpion venom (site 4 toxin) was suppressed even after the extensive washout of NS-7, and veratridine-induced 22Na+ influx remained depressed even at higher concentration of veratridine; however, either ,- or ,-scorpion venom, or Ptychodiscus brevis toxin-3 (site 5 toxin) enhanced veratridine-induced 22Na+ influx as in nontreated cells. These results suggest that in the acute treatment, NS-7 binds to the site 2 and reversibly inhibits Na+ channels, thereby reducing Ca2+ channel gating and catecholamine secretion. Chronic treatment with NS-7 up-regulates cell surface Na+ channels via translational and externalization events, but persistently inhibits Na+ channel gating without impairing the cooperative interaction between the functional domains of Na+ channels. British Journal of Pharmacology (2000) 131, 779,787; doi:10.1038/sj.bjp.0703622 [source] | ||||||||||