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The architecture of the pore-region of a voltage-gated K + channel, Kv1.3, was probed using four high affinity scorpion toxins as molecular calipers. We established the structural relatedness of these toxins by solving the structures of kaliotoxin and margatoxin and comparing them with the published structure of charybdotoxin; a homology model of noxiustoxin was then developed. Complementary...
The lateral nucleus of the amygdala (LA) is the first site in the amygdala where the plasticity underlying fear conditioning could occur. We simultaneously recorded from multiple LA neurons in freely moving rats during fear conditioning trials in which tones were paired with foot shocks. Conditioning significantly increased the magnitude of tone-elicited response (often within the first several trials),...
Extracellular Mg 2+ , which blocks NMDA channels in a voltage-dependent manner and increases the receptor's affinity for glycine, is shown here to potentiate NMDA responses at saturating glycine concentrations. This potentiation, induced by millimolar concentrations of Mg 2+ , is not mimicked by Ca 2+ and Ba 2+ and is voltage independent. The potentiation is variable...
Activation of G protein-gated K + channels by G protein-coupled receptors contributes to parasympathetic regulation of heart rate in the atrium and inhibitory postsynaptic potentials in the peripheral and central nervous system. Having found that G βγ activates the cloned GIRK1 channel, we now report evidence for direct binding of G βγ to both the N-terminal hydrophilic domain...
Transgenic FVB/N mice overexpressing human (Hu) or mouse (Mo) Alzheimer amyloid precursor protein (APP 695 ) die early and develop a CNS disorder that includes neophobia and impaired spatial alternation, with diminished glucose utilization and astrogliosis mainly in the cerebrum. Age at onset of neophobia and age at death decrease with increasing levels of brain APP. HuAPP transgenes induce...
Inward rectifier potassium channels are found in the heart and CNS, where they are critical for the modulation and maintenance of cellular excitability. We present evidience that the inward rectifier potassium channel HIR is modulated by extracellular pH in the physiological rante. We show that proton-induced changes in HIR single-channel conductance underline the HIR pH sensitivity seen on the macroscopic...
huckebein encodes a putative zinc finger protein expressed in a subset of Drosophila CNS precursors, including the NB 4-2/GMC 4-2a/RP2 cell lineage. Inhuckebein mutant embryos, GMC 4-2a does not express the cell fate marker EVEN-SKIPPED; conversely,huckebein overexpression produces a duplicate EVEN-SKIPPED-positive GMC 4-2a. We use Dil to trace the entire NB 4-2 lineage in wild-type andhuckebein mutant...
Ca 2+ -triggered exocytosis was studied in single rat melanotrophs and bovine chromaffin cells by capacitance measurements. Sustained exocytosis required MgATP, but even in the absence of MgATP, Ca 2+ could trigger exocytosis of 2700 granules in a typical melanotroph and of 840 granules in a chromaffin cell. Granules undergoing ATP-independent exocytosis were similar in number to those...
Immunocytochemical evidence for localized distribution of theNa + /Ca 2+ exchange protein in nerve terminals of cultured hippocampal cells is presented together with results on the functional relevance of the exchanger in the control of [Ca 2+ ] i and of synaptic vesicle recycling. The monoclonal antibody R3F1, directed against an epitope on the intracellular loop of...
Chimeras of GIRK1 and IRK1, a G protein-insensitive inward rectifier, are activated by coexpression of G βγ if they contain either the N-terminal or part of the C-terminal hydrophilic domain of GIRK1. The N-terminal domain of GIRK1 also facilitates the fast rates of activation and deactivation following m2 muscarinic receptor stimulation. The hydrophobic core of GIRK1 (M1-H5-M2) is important...
Ca 2+ channels display remarkable selectivity and permeability, traditionally attributed to multiple, discrete Ca 2+ binding sites lining the pore. Each of the four pore-forming segments of Ca 2+ channel α 1 subunits contains a glutamate residue that contributes to high-affinity Ca 2+ interactions. Replacement of all four P-region glutamates with glutamine or...
A trinucleotide repeat (CAG) expansion in the huntingtin gene causes Huntington's disease (HD). In brain tissue from HD heterozygotes with adult onset and more clinically severe juvenile onset, where the largest expansions occur, a mutant protein of equivalent intensity to wild-type huntingtin was detected in cortical synaptosomes, indicating that a mutant species is synthesized and transported with...
The contribution of intersynaptic transmitter diffusion to the AMPA receptor EPSC time course was studied in cultured CA1 hippocampal neurons. Reducing release probability 20-fold with cadmium did not affect the time course of the averaged AMPA receptor EPSC, even when receptor desensitization was blocked by cyclothiazide, suggesting that individual synapses contribute independently to the AMPA receptor-mediated...
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