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Channel Mutation (channel + mutation)
Kinds of Channel Mutation Selected AbstractsChannel mutations in Hsp104 hexamer distinctively affect thermotolerance and prion-specific propagationMOLECULAR MICROBIOLOGY, Issue 6 2007Hiroshi Kurahashi Summary The yeast prion [PSI+] represents an aggregated state of the translation termination factor Sup35 resulting in the tendency of ribosomes to readthrough stop codons. In this study, we constructed an auxotrophic chromosomal marker, ura3-197 (nonsense allele), applicable to selection for loss of [PSI+] to [psi,]. Unlike [psi,] yeast strains, [PSI+] yeast strains exhibit nonsense suppression of the ura3-197 allele and are not viable in the presence of 5-fluoroorotic acid (5-FOA) that is converted to a toxic material by the readthrough product of Ura3. We selected 20 5-FOA-resistant, loss-of-[PSI+], mutants spontaneously or by transposon-mediated mutagenesis from ura3-197[PSI+] cells. All of the 20 [psi,] isolates were affected in Hsp104, a protein-remodelling factor. Although most of them were disabled in a normal Hsp104 function for thermotolerance, three single mutants, L462R, P557L and D704N, remained thermotolerant. Importantly, L462R and D704N also eliminate other yeast prions [URE3] and [PIN+], while P557L does not, suggesting that Hsp104 harbours a unique activity to prion propagation independent of its function in thermotolerance. The mutations that are specific to prion propagation are clustered around the lateral channel of the Hsp104 hexamer, suggesting a crucial and specific role of this channel for prion propagation. [source] Reduced aggression in AMPA-type glutamate receptor GluR-A subunit-deficient miceGENES, BRAIN AND BEHAVIOR, Issue 5 2004O. Y. Vekovischeva The importance of AMPA-type glutamate receptors has been demonstrated in neuronal plasticity and in adaptation to drugs of abuse. We studied the involvement of AMPA receptors in social interaction and anxiety and found that in several paradigms of agonistic behavior naïve male mice deficient for the GluR-A subunit- containing AMPA receptors are less aggressive than wild-type littermates. GluR-A deficient mice and wild-type littermates exhibited similar basic behavior and reflexes as monitored by observational Irwin's test, but they tended to be less anxious in elevated plus-maze and light-dark tests. Maternal aggression or male-female encounters were not affected which suggests that male hormones are involved in the expression of suppressed aggressiveness. However, testosterone levels and brain monoamines can be excluded and found to be similar between GluR-A deficient and wild-type littermates. The reduced AMPA receptor levels caused by the lack of the GluR-A subunit, and measured by a 30% reduction in hippocampal [3H]-S-AMPA binding, seem to be the reason for suppressed male aggressiveness. When we analyzed mice with reduced number of functional AMPA receptors mediated by the genomic introduced GluR-A(Q582R) channel mutation, we observed again male-specific suppressed aggression, providing additional evidence for GluR-A subunit-containing AMPA receptor involvement in aggression. [source] Transmural Action Potential Repolarization Heterogeneity Develops Postnatally in the RabbitJOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, Issue 7 2004Ph.D., SALIM F. IDRISS M.D. Introduction: In the hereditary long QT syndrome, arrhythmia risk changes with age despite the presence of an ion channel mutation throughout development. Age-dependent changes in the transmural dispersion of repolarization may modulate this vulnerability. We recorded cardiac action potentials in infant, periadolescent, and adult rabbit myocardium to determine if transmural heterogeneities in repolarization are developmentally determined. Methods and Results: Arterially perfused ventricular preparations were studied from 2-week (n = 7), 7-week (n = 7), and adult (n = 6) NZW rabbits. Action potentials were recorded with microelectrodes in five regions: epicardium (epi), subepicardium (subepi), midwall (mid), subendocardium (subendo), and endocardium (endo) during endocardial S1 pacing at cycle lengths of 2,000, 1,000, and 500 ms. At 2 weeks, the transmural APD90 profile was flat. With age, APD prolongation from subepi to endo created a transmural repolarization gradient. At 7 weeks, APD90 was significantly longer at subendo [204 ± 2 ms (mean ± SE) 2,000-ms cycle length, P < 0.05] vs both endo (193 ± 2 ms) and epi (172 ± 2 ms), causing a heterogeneous transmural APD90 gradient. In adults, the transmural gradient was a smooth continuum such that APD was shortest in epicardium and longest in endocardium. Conclusion: The transmural distribution of APD is developmentally determined. Tissue-specific age-dependent changes in APD can result in transmural repolarization heterogeneity. These age-related effects may modulate arrhythmia vulnerability during development. (J Cardiovasc Electrophysiol, Vol. 15, pp. 795-801, July 2004) [source] A cardiac sodium channel mutation identified in Brugada syndrome associated with atrial standstillJOURNAL OF INTERNAL MEDICINE, Issue 1 2004N. Takehara Abstract., Takehara N, Makita N, Kawabe J, Sato N, Kawamura Y, Kitabatake A, Kikuchi K (Asahikawa Medical College, Asahikawa; Hokkaido University Graduate School of Medicine, Sapporo, Japan; and Cardiovascular Research Institute, Newark, NY, USA). A cardiac sodium channel mutation identified in Brugada syndrome associated with atrial standstill (Case Report). J Intern Med 2004; 255: 137,142. Mutations in the cardiac Na+ channel gene SCN5A are responsible for multiple lethal ventricular arrhythmias including Brugada syndrome and congenital long QT syndrome. Here we report a case of Brugada syndrome with ST elevation in the right precordial and inferior leads accompanied by atrial standstill and spontaneous ventricular fibrillation. Atrial standstill and J wave elevation were provoked by procainamide. Genetic analysis revealed a missense mutation (R367H) in SCN5A. The resultant mutant Na+ channel was nonfunctional when expressed heterologously in Xenopus oocytes. Our study suggests that genetic defects in SCN5A may be associated with atrial standstill in combination with ventricular arrhythmias. [source] Paramyotonia congenita due to a de novo mutation: A case reportMUSCLE AND NERVE, Issue 2 2003Takayasu Fukudome MD Abstract A Japanese man with a negative family history of paramyotonia congenita (PMC) was evaluated for symptoms of cold-induced weakness and stiffness. Exercise testing revealed findings characteristic of PMC, and a genetic analysis was therefore performed. A well-known sodium channel mutation for PMC (T1313M) was identified in the patient, but was absent in his biological parents. These data demonstrate the occurrence of a de novo mutation, suggesting that evaluation for PMC should be performed in patients with typical symptoms even if the family history is negative. Muscle Nerve 28: 232,235, 2003 [source] Neurotoxicity of channel mutations in heterologously expressed ,7-nicotinic acetylcholine receptorsEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 10 2001Ronald J. Lukas Abstract Nicotinic acetylcholine receptors (nAChR) composed of chick ,7 subunits mutated to threonine at amino acid valine-251 in the putative channel-lining M2 domain were expressed heterologously in several neuron-like and non-neuronal mammalian cell lines. Expression of mutant ,7-nAChR is toxic to neuron-like cells of the human neuroblastoma cell lines SH-SY5Y and IMR-32, but not to several other cell types. Growth in the presence of the ,7-nAChR antagonist methyllycaconitine (MLA) protects against neurotoxicity, as does gradual downregulation of functional, mutant ,7-nAChR in surviving transfected SH-SY5Y cells. Relative to wild-type ,7-nAChR, functional ,7-nAChR mutants show a higher affinity for agonists, slower rates of desensitization, and sensitivity to dihydro-,-erythroidine (DH,E) as an agonist, but they retain sensitivity to MLA as a competitive antagonist. These findings demonstrate that expression of hyperfunctional, mutant forms of Ca2+ -permeable ,7-nAChR is toxic to neuron-like cells. [source] Computational physiology and the physiome projectEXPERIMENTAL PHYSIOLOGY, Issue 1 2004Edmund J. Crampin Bioengineering analyses of physiological systems use the computational solution of physical conservation laws on anatomically detailed geometric models to understand the physiological function of intact organs in terms of the properties and behaviour of the cells and tissues within the organ. By linking behaviour in a quantitative, mathematically defined sense across multiple scales of biological organization , from proteins to cells, tissues, organs and organ systems , these methods have the potential to link patient-specific knowledge at the two ends of these spatial scales. A genetic profile linked to cardiac ion channel mutations, for example, can be interpreted in relation to body surface ECG measurements via a mathematical model of the heart and torso, which includes the spatial distribution of cardiac ion channels throughout the myocardium and the individual kinetics for each of the approximately 50 types of ion channel, exchanger or pump known to be present in the heart. Similarly, linking molecular defects such as mutations of chloride ion channels in lung epithelial cells to the integrated function of the intact lung requires models that include the detailed anatomy of the lungs, the physics of air flow, blood flow and gas exchange, together with the large deformation mechanics of breathing. Organizing this large body of knowledge into a coherent framework for modelling requires the development of ontologies, markup languages for encoding models, and web-accessible distributed databases. In this article we review the state of the field at all the relevant levels, and the tools that are being developed to tackle such complexity. Integrative physiology is central to the interpretation of genomic and proteomic data, and is becoming a highly quantitative, computer-intensive discipline. [source] Sudden Cardiac Death and Inherited Arrhythmia SyndromesJOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, Issue 2005ANDREA SARKOZY M.D. Sudden cardiac death (SCD) at youth is rare and is often caused by inherited cardiac disorders. This review focuses on the genetic background of inherited primary electrical diseases, the so-called "channelopathies." Following a short clinical description of each syndrome, the recent findings in the genetics of long QT syndrome, short QT syndrome, isolated cardiac conduction defect, familial sick sinus syndrome, familial atrial fibrillation, cathecholaminergic polymorphic ventricular tachycardia, familial Wolff-Parkinson-White (WPW) syndrome, and Brugada syndrome are discussed. The currently proposed theoretical model of overlapping phenotypes in SCN5A sodium channel mutations is presented. The recent data indicate that advances in molecular genetics, experimental and clinical electrophysiology shed some light on the genetic background of primary electrical diseases. However, it is also becoming clear that the process from a mutation of a gene to the clinical presentation of a patient is currently only partially understood and extremely complex. [source] | |||||||||||||