Changes of voltage-gated ion channels and ligand-gated receptor channels caused by mutation or autoimmune attack are the cause of so-called channelopathies in the central and peripheral nervous system. We present the pathophysiology of channelopathies of the neuromuscular junction in terms of loss-of-function and gain-of-function principles. Autoantibodies generally have reduced access to the central nervous system, but in some cases this is enough to cause disease. A review is provided of recent findings implicating autoantibodies against ligand-activated receptor channels and potassium channels in psychiatric and neurological disorders, including schizophrenia and limbic encephalitis. The emergence of channelopathy-related neuropsychiatric disorders has implications for research and practice.
Showing posts with label channels. Show all posts
Showing posts with label channels. Show all posts
Bisphenol a inhibits voltage-activated Ca2+ channels in vitro: mechanisms and structural requirements.
Bisphenol A (BPA), a high volume production chemical compound attracts growing attention as a health-relevant xenobiotic in humans. It can directly bind to hormone receptors, enzymes, and ion channels to become biologically active. In this study we show that BPA acts as a potent blocker of voltage-activated Ca(2+) channels. We determined the mechanisms of block and the structural elements of BPA essential for its action. Macroscopic Ba(2+)/ Ca(2+) currents through native L-, N-, P/Q-, T-type Ca(2+) channels in rat endocrine GH(3) cells, mouse dorsal root ganglion neurons or cardiac myocytes, and recombinant human R-type Ca(2+) channels expressed in human embryonic kidney (HEK) 293 cells were rapidly and reversibly inhibited by BPA with similar potency (EC(50) values: 26-35 μM). Pharmacological and biophysical analysis of R-type Ca(2+) channels revealed that BPA interacts with the extracellular part of the channel protein. Its action does not require intracellular signaling pathways, is neither voltage- nor use-dependent, and does not affect channel gating. This indicates that BPA interacts with the channel in its resting state by directly binding to an external site outside the pore-forming region. Structure-effect analyses of various phenolic and bisphenolic compounds revealed that 1) a double-alkylated (R-C(CH(3))(2)-R, R-C(CH(3))(CH(2)CH(3))-R), or double-trifluoromethylated sp(3)-hybridized carbon atom between the two aromatic rings and 2) the two aromatic moieties in angulated orientation are optimal for BPA's effectiveness. Since BPA highly pollutes the environment and is incorporated into the human organism, our data may provide a basis for future studies relevant for human health and development.
Perhaps relevant to numerous channelopathies.
Perhaps relevant to numerous channelopathies.
RSNA press release: Sodium Buildup in Brain Linked to Disability in Multiple Sclerosis
A buildup of sodium in the brain detected by magnetic resonance imaging (MRI) may be a biomarker for the degeneration of nerve cells that occurs in patients with multiple sclerosis (MS), according to a new study published online in the journal Radiology. The study found that patients with early-stage MS showed sodium accumulation in specific brain regions, while patients with more advanced disease showed sodium accumulation throughout the whole brain. Sodium buildup in motor areas of the brain correlated directly to the degree of disability seen in the advanced-stage patients.
Sea anemones venom key to Multiple Sclerosis treatment
(Medical Xpress) -- Sea anemones use venomous stinging tentacles to stun their prey, but one component of that venom is being used by researchers to treat the debilitating effects of Multiple Sclerosis (MS).
A new class of drug treatment is about to commence clinical trials, as the result of a decade-long investigation by Professor Ray Norton, from the Monash Institute of Pharmaceutical Sciences and his collaborators, who in the mid 1990s found a component of venom called ShK in the Caribbean sea anemone. The researchers found ShK blocks the Kv1.3 potassium channel located in white blood cells, known as T-cells, which are known to produce nerve damage in MS, one of the most common and debilitating diseases of the nervous system.
A new class of drug treatment is about to commence clinical trials, as the result of a decade-long investigation by Professor Ray Norton, from the Monash Institute of Pharmaceutical Sciences and his collaborators, who in the mid 1990s found a component of venom called ShK in the Caribbean sea anemone. The researchers found ShK blocks the Kv1.3 potassium channel located in white blood cells, known as T-cells, which are known to produce nerve damage in MS, one of the most common and debilitating diseases of the nervous system.
Regulation of Neuronal Proapoptotic Potassium Currents by the Hepatitis C Virus Nonstructural Protein 5A
Apoptosis-enabling neuronal potassium efflux is mediated by an enhancement of K+ currents. In cortical neurons, increased currents are triggered by dual phosphorylation of Kv2.1 by Src and p38 at channel residues Y124 and S800. It was recently shown that a K+ current surge is also present in hepatocytes undergoing apoptosis, and that the hepatitis C virus (HCV) nonstructural protein 5A (NS5A) could inhibit Kv2.1-mediated currents and block cell death. Here, we show that NS5A1b (from HCV genotype 1b) expression in rat neurons depresses delayed rectifier potassium currents, limits the magnitude of the K+ current surge following exposure to activated microglia, and is neuroprotective. In a non-neuronal recombinant expression system, cells expressing Kv2.1 mutated at residue Y124, but not S800 mutants, are insensitive to NS5A1b-mediated current inhibition. Accordingly, NS5A1b coexpression prevents phosphorylation of wild-type Kv2.1 by Src at Y124, but is unable to inhibit p38 phosphorylation of the channel at S800. The actions of the viral protein are genotype-selective, as NS5A1a does not depress neuronal potassium currents nor inhibit Src phosphorylation of Kv2.1. Our results indicate that NS5A1b limits K+ currents following injury, leading to increased neuronal viability. NS5A1b may thus serve as a model for a new generation of neuroprotective agents.
Rare condition Timothy syndrome may give clues to autism - Health News - NHS Choices
Timothy syndrome is associated with a defect in the calcium channel CACNA1C, also associated with autism .
Genetic testing in epilepsy -- it takes more than 1 gene
Klassen et al, Cell Paper
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