Home About us Contact
|
Home About us Contact | ||
|
|
||
Fast Inactivation (fast + inactivation)
Selected AbstractsEpisodic ataxia type 1 mutations in the KCNA1 gene impair the fast inactivation properties of the human potassium channels Kv1.4-1.1/Kv,1.1 and Kv1.4-1.1/Kv,1.2EUROPEAN JOURNAL OF NEUROSCIENCE, Issue 11 2006Paola Imbrici Abstract Episodic ataxia type 1 (EA1) is an autosomal dominant neurological disorder characterized by constant muscle rippling movements (myokymia) and episodic attacks of ataxia. Several heterozygous point mutations have been found in the coding sequence of the voltage-gated potassium channel gene KCNA1 (hKv1.1), which alter the delayed-rectifier function of the channel. Shaker -like channels of different cell types may be formed by unique hetero-oligomeric complexes comprising Kv1.1, Kv1.4 and Kv,1.x subunits. Here we show that the human Kv,1.1 and Kv,1.2 subunits modulated the functional properties of tandemly linked Kv1.4-1.1 wild-type channels expressed in Xenopus laevis oocytes by (i) increasing the rate and amount of N-type inactivation, (ii) slowing the recovery rate from inactivation, (iii) accelerating the cumulative inactivation of the channel and (iv) negatively shifting the voltage dependence of inactivation. To date, the role of the human Kv1.4-1.1, Kv1.4-1.1/Kv,1.1 and Kv1.4-1.1/Kv,1.2 channels in the aetiopathogenesis of EA1 has not been investigated. Here we also show that the EA1 mutations E325D, V404I and V408A, which line the ion-conducting pore, and I177N, which resides within the S1 segment, alter the fast inactivation and repriming properties of the channels by decreasing both the rate and degree of N-type inactivation and by accelerating the recovery from fast inactivation. Furthermore, the E325D, V404I and I177N mutations shifted the voltage dependence of the steady-state inactivation to more positive potentials. The results demonstrate that the human Kv,1.1 and Kv,1.2 subunits regulate the proportion of wild-type Kv1.4-1.1 channels that are available to open. Furthermore, EA1 mutations alter heteromeric channel availability which probably modifies the integration properties and firing patterns of neurones controlling cognitive processes and body movements. [source] Differential sensitivity of sodium channels from the central and peripheral nervous system to the scorpion toxins Lqh-2 and Lqh-3EUROPEAN JOURNAL OF NEUROSCIENCE, Issue 4 2002Haijun Chen Abstract The scorpion ,-toxins Lqh-2 and Lqh-3, isolated from the venom of the Israeli yellow scorpion Leiurus quinquestriatus hebraeus, were previously shown to be very potent in removing fast inactivation of rat skeletal muscle sodium channels (Chen et al., 2000). Here, we show that tetrodotoxin-sensitive neuronal channels NaV1.2 and NaV1.7, which are mainly expressed in mammalian central and peripheral nervous systems, respectively, are differentially sensitive to these two toxins. rNaV1.2 and hNaV1.7 channels were studied with patch-clamp methods upon expression in mammalian cells. While Lqh-3 was about 100-times more potent in removing inactivation in hNaV1.7 channels compared with rNaV1.2, Lqh-2 was about 20-times more active in the other direction. Site-directed mutagenesis showed that the differences in the putative binding sites for these toxins, the S3-4 linkers of domain 4, are of major importance for Lqh-3, but not for Lqh-2. [source] A new class of neurotoxin from wasp venom slows inactivation of sodium currentEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 6 2000Yoshinori Sahara Abstract The effects of ,-pompilidotoxin (,-PMTX), a new neurotoxin isolated from the venom of a solitary wasp, were studied on the neuromuscular synapses in lobster walking leg and the rat trigeminal ganglion (TG) neurons. Paired intracellular recordings from the presynaptic axon terminals and the innervating lobster leg muscles revealed that ,-PMTX induced long bursts of action potentials in the presynaptic axon, which resulted in facilitated excitatory and inhibitory synaptic transmission. The action of ,-PMTX was distinct from that of other known facilitatory presynaptic toxins, including sea anemone toxins and ,-scorpion toxins, which modify the fast inactivation of Na+ current. We further characterized the action of ,-PMTX on Na+ channels by whole-cell recordings from rat trigeminal neurons. We found that ,-PMTX slowed the Na+ channels inactivation process without changing the peak current,voltage relationship or the activation time course of tetrodotoxin (TTX)-sensitive Na+ currents, and that ,-PMTX had voltage-dependent effects on the rate of recovery from Na+ current inactivation and deactivating tail currents. The results suggest that ,-PMTX slows or blocks conformational changes required for fast inactivation of the Na+ channels on the extracellular surface. The simple structure of ,-PMTX, consisting of 13 amino acids, would be advantageous for understanding the functional architecture of Na+ channel protein. [source] Protein phosphatase 2A,negative regulation of the protective signaling pathway of Ca2+/CaM-dependent ERK activation in cerebral ischemiaJOURNAL OF NEUROSCIENCE RESEARCH, Issue 12 2008Jie Zhao Abstract Extracellular-signal-regulated kinase (ERK) undergoes rapid inactivation following the intense activation evoked by cerebral ischemia and reperfusion. However, the precise mechanism of this inactivation has not been elucidated. To investigate how phosphatases regulate the ERK cascade following ischemia, the PP2A inhibitors cantharidin and okadaic acid were administrated to the CA1 subregion of the rat hippocampus. The resulting sustained ERK activity implies that PP2A is a major phosphatase contributing to the rapid inactivation, but not activation, of ERK following cerebral ischemia. The increase in PP2A activity induced by ceramide has a weak effect on the activation of Raf via dephosphorylation of Ser259 in response to ischemia. In contrast, ketamine (Keta) and cyclosporine A (CsA), two chemicals that block calcium signal in ischemia, decrease ERK activity by blocking Raf dephosphorylation of Ser259. We also observed that activation of an upstream protein, Ras-GRF, leads to calcium/calmodulin-dependent activation of the ERK signaling cascade in response to ischemic stimuli. In addition, the activity of cyclic AMP response element-binding protein (CREB) and estrogen receptor , (ER,), target proteins of ERK and protective elements against ischemic lesion, parallels the activity of ERK. These data indicate that PP2A plays a significant role in blocking the protective effect induced by the ERK kinase pathway and that fast inactivation of ERK is the result of cross talk between calcium/calmodulin-dependent, positively regulated signal cascades and a ceramide-dependent negative signaling pathway. © 2008 Wiley-Liss, Inc. [source] TEMPERATURE INDUCED PHOTOINHIBITION IN OUTDOOR CULTURES OF MONODUS SUBTERRANEUSJOURNAL OF PHYCOLOGY, Issue 2000A. Vonshak Outdoor algal cultures are continuously exposed to changes in environmental conditions, particularly irradiance and temperature. While the changes in light intensity take place in a range of one to two hours, the increase in temperature is a slower process and takes about four to five hours. This de-synchronization between the two important environmental factors governing photosynthesis and growth of algae results in a unique stress condition where photoinhibition can be induced at relatively low light intensity. Outdoors the early morning culture temperature was found to be about 12 to 14° C, and reaches 25 to 28° C at mid-day. In an experiment, such a natural temperature regime was compared to another one in which the morning temperature of the culture was increased to 20° C by using a heating system. A fast decline in the maximal photochemical efficiency of PSII (Fv/Fm) was observed starting as soon as sunrise. The decline was faster in the non-heated culture and was to a lower value. The diurnal changes in the electron transfer rate (ETR) and in the non-photochemical quenching (NPQ) of the cultures, indicated that the early morning exposure of cells to sub-optimal temperature results in a fast inactivation of PSII activity which was reflected in an inhibition of the photosynthetic activity even when the two cultures finally reached the same temperature at mid-day. Thus, under the same light and temperature mid-day conditions the ETR was higher and the NPQ was significantly lower in the heated culture. Significant changes in productivity of the cultures also were observed. [source] Sodium channel inactivation defects are associated with acetazolamide-exacerbated hypokalemic periodic paralysisANNALS OF NEUROLOGY, Issue 3 2001Saïd Bendahhou PhD A novel mutation in a family with hypokalemic periodic paralysis is described. The mutation R672S is located in the voltage sensor segment S4 of domain II in the SCN4A gene encoding the human skeletal muscle voltage-gated sodium channel. Functional expression of the R672S channels in human embryonic kidney 293 cells revealed a small but significant hyperpolarizing shift in the steady-state fast inactivation, and a dramatic enhancement in channel slow inactivation. These two defects are mainly due to a slow recovery of the mutant channels from fast and/or slow inactivation. Our data may help explain the mechanism underlying hypokalemic periodic paralysis and the patient's worsening from acetazolamide. [source] Solution Structure of , -Am2766: A Highly Hydrophobic , -Conotoxin from Conus amadis That Inhibits Inactivation of Neuronal Voltage-Gated Sodium ChannelsCHEMISTRY & BIODIVERSITY, Issue 4 2005Siddhartha The three-dimensional (3D) NMR solution structure (MeOH) of the highly hydrophobic , -conotoxin , -Am2766 from the molluscivorous snail Conus amadis has been determined. Fifteen converged structures were obtained on the basis of 262 distance constraints, 25 torsion-angle constraints, and ten constraints based on disulfide linkages and H-bonds. The root-mean-square deviations (rmsd) about the averaged coordinates of the backbone (N, C,, C) and (all) heavy atoms were 0.62±0.20 and 1.12±0.23,Å, respectively. The structures determined are of good stereochemical quality, as evidenced by the high percentage (100%) of backbone dihedral angles that occupy favorable and additionally allowed regions of the Ramachandran map. The structure of , -Am2766 consists of a triple-stranded antiparallel , -sheet, and of four turns. The three disulfides form the classical ,inhibitory cysteine knot' motif. So far, only one tertiary structure of a , -conotoxin has been reported; thus, the tertiary structure of , -Am2766 is the second such example. Another Conus peptide, Am2735 from C. amadis, has also been purified and sequenced. Am2735 shares 96% sequence identity with , -Am2766. Unlike , -Am2766, Am2735 does not inhibit the fast inactivation of Na+ currents in rat brain Nav1.2 Na+ channels at concentrations up to 200,nM. [source] | ||||||||||