Home About us Contact
|
Home About us Contact | ||
|
|
||
Voltage-gated Na+ Channels (voltage-gated + na+_channel)
Selected AbstractsHemiconvulsion,hemiplegia syndrome in a patient with severe myoclonic epilepsy in infancyEPILEPSIA, Issue 9 2009Takafumi Sakakibara Summary We report a 2-year-old girl who had repeated febrile or afebrile seizures since infancy. Prolonged left/right hemiconvulsions and myoclonus of the eyelids/extremities with generalization to tonic,clonic seizures, were refractory to antiepileptic agents. At age 1 year and 4 months, she contracted rotavirus infection, and developed status epilepticus with persistent right hemiclonic seizures. Left unilateral brain edema with subsequent emergence of cortical laminar necrosis and white matter lesions, and progressive atrophy of the left cerebral hemisphere were noted during this period. She showed residual right hemiparesis and mild intellectual disability, and had generalized/eyelid myoclonia and hot water epilepsy after a 5-month seizure-free period. Analysis for SCN1A, the gene encoding the neuronal voltage-gated Na+ channel ,1 subunit revealed a nonsense mutation, R1892X. These indicate the potential risk in patients with severe myoclonic epilepsy in infancy (SMEI) to develop hemiconvulsion,hemiplegia (HH) syndrome. SCN1A mutations may need to be further explored in patients with HH syndrome without features of SMEI. [source] Recent progress on the molecular organization of myelinated axonsJOURNAL OF THE PERIPHERAL NERVOUS SYSTEM, Issue 1 2002Steven S. Scherer Abstract The structure of myelinated axons was well described 100 years ago by Ramón y Cajal, and now their molecular organization is being revealed. The basal lamina of myelinating Schwann cells contains laminin-2, and their abaxonal/outer membrane contains two laminin-2 receptors, ,6,4 integrin and dystroglycan. Dystroglycan binds utrophin, a short dystrophin isoform (Dp116), and dystroglycan-related protein 2 (DRP2), all of which are part of a macromolecular complex. Utrophin is linked to the actin cytoskeleton, and DRP2 binds to periaxin, a PDZ domain protein associated with the cell membrane. Non-compact myelin,found at incisures and paranodes,contains adherens junctions, tight junctions, and gap junctions. Nodal microvilli contain F-actin, ERM proteins, and cell adhesion molecules that may govern the clustering of voltage-gated Na+ channels in the nodal axolemma. Nav1.6 is the predominant voltage-gated Na+ channel in mature nerves, and is linked to the spectrin cytoskeleton by ankyrinG. The paranodal glial loops contain neurofascin 155, which likely interacts with heterodimers composed of contactin and Caspr/paranodin to form septate-like junctions. The juxtaparanodal axonal membrane contains the potassium channels Kv1.1 and Kv1.2, their associated ,2 subunit, as well as Caspr2. Kv1.1, Kv1.2, and Caspr2 all have PDZ binding sites and likely interact with the same PDZ binding protein. Like Caspr, Caspr2 has a band 4.1 binding domain, and both Caspr and Caspr2 probably bind to the band 4.1B isoform that is specifically found associated with the paranodal and juxtaparanodal axolemma. When the paranode is disrupted by mutations (in cgt -, contactin -, and Caspr -null mice), the localization of these paranodal and juxtaparanodal proteins is altered: Kv1.1, Kv1.2, and Caspr2 are juxtaposed to the nodal axolemma, and this reorganization is associated with altered conduction of myelinated fibers. Understanding how axon-Schwann interactions create the molecular architecture of myelinated axons is fundamental and almost certainly involved in the pathogenesis of peripheral neuropathies. [source] Estrogen and non-genomic upregulation of voltage-gated Na+ channel activity in MDA-MB-231 human breast cancer cells: Role in adhesion,JOURNAL OF CELLULAR PHYSIOLOGY, Issue 2 2010Scott P. Fraser External (but not internal) application of ,-estradiol (E2) increased the current amplitude of voltage-gated Na+ channels (VGSCs) in MDA-MB-231 human breast cancer (BCa) cells. The G-protein activator GTP-,-S, by itself, also increased the VGSC current whilst the G-protein inhibitor GDP-,-S decreased the effect of E2. Expression of GPR30 (a G-protein-coupled estrogen receptor) in MDA-MB-231 cells was confirmed by PCR, Western blot and immunocytochemistry. Importantly, G-1, a specific agonist for GPR30, also increased the VGSC current amplitude in a dose-dependent manner. Transfection and siRNA-silencing of GPR30 expression resulted in corresponding changes in GPR30 protein expression but only internally, and the response to E2 was not affected. The protein kinase A inhibitor, PKI, abolished the effect of E2, whilst forskolin, an adenylate cyclase activator, by itself, increased VGSC activity. On the other hand, pre-incubation of the MDA-MB-231 cells with brefeldin A (a trans -Golgi protein trafficking inhibitor) had no effect on the E2-induced increase in VGSC amplitude, indicating that such trafficking (,externalisation') of VGSC was not involved. Finally, acute application of E2 decreased cell adhesion whilst the specific VGSC blocker tetrodotoxin increased it. Co-application of E2 and tetrodotoxin inhibited the effect of E2 on cell adhesion, suggesting that the effect of E2 was mainly through VGSC activity. Pre-treatment of the cells with PKI abolished the effect of E2 on adhesion, consistent with the proposed role of PKA. Potential implications of the E2-induced non-genomic upregulation of VGSC activity for BCa progression are discussed. J. Cell. Physiol. 224: 527,539, 2010. © 2010 Wiley-Liss, Inc. [source] Recent progress on the molecular organization of myelinated axonsJOURNAL OF THE PERIPHERAL NERVOUS SYSTEM, Issue 1 2002Steven S. Scherer Abstract The structure of myelinated axons was well described 100 years ago by Ramón y Cajal, and now their molecular organization is being revealed. The basal lamina of myelinating Schwann cells contains laminin-2, and their abaxonal/outer membrane contains two laminin-2 receptors, ,6,4 integrin and dystroglycan. Dystroglycan binds utrophin, a short dystrophin isoform (Dp116), and dystroglycan-related protein 2 (DRP2), all of which are part of a macromolecular complex. Utrophin is linked to the actin cytoskeleton, and DRP2 binds to periaxin, a PDZ domain protein associated with the cell membrane. Non-compact myelin,found at incisures and paranodes,contains adherens junctions, tight junctions, and gap junctions. Nodal microvilli contain F-actin, ERM proteins, and cell adhesion molecules that may govern the clustering of voltage-gated Na+ channels in the nodal axolemma. Nav1.6 is the predominant voltage-gated Na+ channel in mature nerves, and is linked to the spectrin cytoskeleton by ankyrinG. The paranodal glial loops contain neurofascin 155, which likely interacts with heterodimers composed of contactin and Caspr/paranodin to form septate-like junctions. The juxtaparanodal axonal membrane contains the potassium channels Kv1.1 and Kv1.2, their associated ,2 subunit, as well as Caspr2. Kv1.1, Kv1.2, and Caspr2 all have PDZ binding sites and likely interact with the same PDZ binding protein. Like Caspr, Caspr2 has a band 4.1 binding domain, and both Caspr and Caspr2 probably bind to the band 4.1B isoform that is specifically found associated with the paranodal and juxtaparanodal axolemma. When the paranode is disrupted by mutations (in cgt -, contactin -, and Caspr -null mice), the localization of these paranodal and juxtaparanodal proteins is altered: Kv1.1, Kv1.2, and Caspr2 are juxtaposed to the nodal axolemma, and this reorganization is associated with altered conduction of myelinated fibers. Understanding how axon-Schwann interactions create the molecular architecture of myelinated axons is fundamental and almost certainly involved in the pathogenesis of peripheral neuropathies. [source] Complex interplay between glutamate receptors and intracellular Ca2+ stores during ischaemia in rat spinal cord white matterTHE JOURNAL OF PHYSIOLOGY, Issue 1 2006Mohamed Ouardouz Electrophysiological recordings of propagated compound action potentials (CAPs) and axonal Ca2+ measurements using confocal microscopy were used to study the interplay between AMPA receptors and intracellullar Ca2+ stores in rat spinal dorsal columns subjected to in vitro combined oxygen and glucose deprivation (OGD). Removal of Ca2+ or Na+ from the perfusate was protective after 30 but not 60 min of OGD. TTX was ineffective with either exposure, consistent with its modest effect on ischaemic depolarization. In contrast, AMPA antagonists were very protective, even after 60 min of OGD where 0Ca2++ EGTA perfusate was ineffective. Similarly, blocking ryanodine receptor-mediated Ca2+ mobilization from internal stores (0Ca2++ nimodipine or 0Ca2++ ryanodine), or inositol 1,4,5-trisphosphate (IP3)-dependent Ca2+ release (block of group 1 metabotropic glutamate receptors with 1-aminoindan-1,5-dicarboxylic acid, inhibition of phospholipase C with U73122 or IP3 receptor block with 2APB; each in 0Ca2+) were each very protective, with the combination resulting in virtually complete functional recovery after 1 h OGD (97 ± 32% CAP recovery versus 4 ± 6% in artificial cerebrospinal fluid). AMPA induced a rise in Ca2+ concentration in normoxic axons, which was greatly reduced by blocking ryanodine receptors. Our data therefore suggest a novel and surprisingly complex interplay between AMPA receptors and Ca2+ mobilization from intracellular Ca2+ stores. We propose that AMPA receptors may not only allow Ca2+ influx from the extracellular space, but may also significantly influence Ca2+ release from intra-axonal Ca2+ stores. In dorsal column axons, AMPA receptor-dependent mechanisms appear to exert a greater influence than voltage-gated Na+ channels on functional outcome following OGD. [source] Stereoselective modulatory actions of oleamide on GABAA receptors and voltage-gated Na+ channels in vitro: a putative endogenous ligand for depressant drug sites in CNSBRITISH JOURNAL OF PHARMACOLOGY, Issue 2 2000Bernard Verdon cis -9,10-octadecenoamide (,oleamide') accumulates in CSF on sleep deprivation. It induces sleep in animals (the trans form is inactive) but its cellular actions are poorly characterized. We have used electrophysiology in cultures from embryonic rat cortex and biochemical studies in mouse nerve preparations to address these issues. Twenty ,Mcis -oleamide (but not trans) reversibly enhanced GABAA currents and depressed the frequency of spontaneous excitatory and inhibitory synaptic activity in cultured networks. cis -oleamide stereoselectively blocked veratridine-induced (but not K+ -induced) depolarisation of mouse synaptoneurosomes (IC50, 13.9 ,M). The cis isomer stereoselectively blocked veratridine-induced (but not K+ -induced) [3H]-GABA release from mouse synaptosomes (IC50, 4.6 ,M). At 20 ,Mcis -oleamide, but not trans, produced a marked inhibition of Na+ channel-dependent rises in intrasynaptosomal Ca2+. The physiological significance of these observations was examined by isolating Na+ spikes in cultured pyramidal neurones. Sixty-four ,Mcis -oleamide did not significantly alter the amplitude, rate of rise or duration of unitary action potentials (1 Hz). cis -Oleamide stereoselectively suppressed sustained repetitive firing (SRF) in these cells with an EC50 of 4.1 ,M suggesting a frequency- or state-dependent block of voltage-gated Na+ channels. Oleamide is a stereoselective modulator of both postsynaptic GABAA receptors and presynaptic or somatic voltage-gated Na+ channels which are crucial for synaptic inhibition and conduction. The modulatory actions are strikingly similar to those displayed by sedative or anticonvulsant barbiturates and a variety of general anaesthetics. Oleamide may represent an endogenous modulator for drug receptors and an important regulator of arousal. British Journal of Pharmacology (2000) 129, 283,290; doi:10.1038/sj.bjp.0703051 [source] Binding characteristics of BmK I, an ,-like scorpion neurotoxic polypeptide, on cockroach nerve cord synaptosomesCHEMICAL BIOLOGY & DRUG DESIGN, Issue 4 2000Y.-J. Li Abstract: In this study, the binding characteristics of BmK I, an ,-like neurotoxic polypeptide purified from the venom of the Chinese scorpion Buthus martensi Karsch, were investigated on rat brain and cockroach nerve cord synaptosomes. The results showed that BmK I can bind to a single class of noninteracting binding sites on cockroach nerve cord synaptosomes with medium affinity (Kd = 16.5 ± 4.4 nm) and low binding capacity (Bmax= 1.05 ± 0.23 pmol/mg protein), but lacks specific binding on rat brain synaptosomes. BmK AS, BmK AS-1 (two novel sodium channel-blocking ligands), BmK IT (an excitatory insect-selective toxin) and BmK IT2 (a depressant insect-selective toxin) from the same venom were found to be capable of depressing BmK I binding in cockroach nerve cord synaptosomes, which might be attributed to either allosteric modulation of voltage-gated Na+ channels by these toxic polypeptides or partial overlapping between the receptor binding sites of BmK I and these toxins. This thus supported the notion that ,-like scorpion neurotoxic polypeptides bind to a distinct receptor site on sodium channels, which might be similar to the binding receptor site of ,-type insect toxins, and also related to those of BmK AS type and insect-selective scorpion toxins on insect sodium channels. [source] | |||||||||||||