51 research outputs found
Time-Dependent Block and Resurgent Tail Currents Induced by Mouse ÎČ4154â167 Peptide in Cardiac Na+ Channels
Resurgent tail Na+ currents were first discovered in cerebellar Purkinje neurons. A recent study showed that a 14-mer fragment of a mouse ÎČ4 subunit, ÎČ4154â167, acts as an intracellular open-channel blocker and elicits resurgent currents in Purkinje neurons (Grieco, T.M., J.D. Malhotra, C. Chen, L.L. Isom, and I.M. Raman. 2005. Neuron. 45:233â244). To explore these phenotypes in vitro, we characterized ÎČ4154â167 actions in inactivation-deficient cardiac hNav1.5 Na+ channels expressed in human embryonic kidney 293t cells. Intracellular ÎČ4154â167 from 25â250 ÎŒM elicited a conspicuous time-dependent block of inactivation-deficient Na+ currents at 50 mV in a concentration-dependent manner. On and off rates for ÎČ4154â167 binding were estimated at 10.1 ÎŒMâ1sâ1 and 49.1 sâ1, respectively. Upon repolarization, large tail currents emerged with a slight delay at â140 mV, probably as a result of the rapid unblocking of ÎČ4154â167. Near the activation threshold (approximately â70 mV), resurgent tail currents were robust and long lasting. Likewise, ÎČ4154â167 induces resurgent currents in wild-type hNav1.5 Na+ channels, although to a lesser extent. The inactivation peptide acetyl-KIFMK-amide not only restored the fast inactivation phenotype in hNav1.5 inactivation-deficient Na+ channels but also elicited robust resurgent currents. When modified by batrachotoxin (BTX), wild-type hNav1.5 Na+ channels opened persistently but became resistant to ÎČ4154â167 and acetyl-KIFMK-amide block. Finally, a lysine substitution of a phenylalanine residue at D4S6, F1760, which forms a part of receptors for local anesthetics and BTX, rendered cardiac Na+ channels resistant to ÎČ4154â167. Together, our in vitro studies identify a putative S6-binding site for ÎČ4154â167 within the inner cavity of hNav1.5 Na+ channels. Such an S6 receptor readily explains (1) why ÎČ4154â167 gains access to its receptor as an open-channel blocker, (2), why bound ÎČ4154â167 briefly prevents the activation gate from closing by a âfoot-in-the-doorâ mechanism during deactivation, (3) why BTX inhibits ÎČ4154â167 binding by physical exclusion, and (4) why a lysine substitution of residue F1760 eliminates ÎČ4154â167 binding
Topical amitriptyline in healthy volunteers
Background and Objectives: The antidepressant amitriptyline is used as an adjuvant in the treatment of a variety of chronic pain conditions. This drug interacts with many receptors and ion channels, such as Na Ï© channels. In a randomized, double-blinded, and placebo-controlled trial, we investigated whether amitriptyline also is capable of providing cutaneous analgesia when applied topically in 14 healthy volunteers
Ephedrine Blocks Rat Sciatic Nerve In Vivo and Sodium Channels In Vitro
Background: The sympathomimetic drug ephedrine has been used intrathecally as the sole local anesthetic for labor and delivery. Because ephedrine may be a useful adjuvant to local anesthetics, the authors investigated the local anesthetic properties of ephedrine in a rat sciatic nerve block model and the underlying mechanism in cultured cells stably expressing N
The genetic architecture of the human cerebral cortex
The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder
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The impact of PICALM genetic variations on reserve capacity of posterior cingulate in AD continuum
Phosphatidylinositolbinding clathrin assembly protein (PICALM) gene is one novel genetic player associated with late-onset Alzheimerâs disease (LOAD), based on recent genome wide association studies (GWAS). However, how it affects AD occurrence is still unknown. Brain reserve hypothesis highlights the tolerant capacities of brain as a passive means to fight against neurodegenerations. Here, we took the baseline volume and/or thickness of LOAD-associated brain regions as proxies of brain reserve capacities and investigated whether PICALM genetic variations can influence the baseline reserve capacities and the longitudinal atrophy rate of these specific regions using data from Alzheimerâs Disease Neuroimaging Initiative (ADNI) dataset. In mixed population, we found that brain region significantly affected by PICALM genetic variations was majorly restricted to posterior cingulate. In sub-population analysis, we found that one PICALM variation (C allele of rs642949) was associated with larger baseline thickness of posterior cingulate in health. We found seven variations in health and two variations (rs543293 and rs592297) in individuals with mild cognitive impairment were associated with slower atrophy rate of posterior cingulate. Our study provided preliminary evidences supporting that PICALM variations render protections by facilitating reserve capacities of posterior cingulate in non-demented elderly
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