Slow inactivation does not affect movement of the fast inactivation gate in voltage-gated Na+ channels.

Voltage-gated Na+ channels exhibit two forms of inactivation, one form (fast inactivation) takes effect on the order of milliseconds and the other (slow inactivation) on the order of seconds to minutes. While previous studies have suggested that fast and slow inactivation are structurally independent gating processes, little is known about the relationship between the two. In this study, we probed this relationship by examining the effects of slow inactivation on a conformational marker for fast inactivation, the accessibility of a site on the Na+ channel III-IV linker that is believed to form a part of the fast inactivation particle. When cysteine was substituted for phenylalanine at position 1304 in the rat skeletal muscle sodium channel (microl), application of [2-(trimethylammonium)ethyl]methanethiosulfonate (MTS-ET) to the cytoplasmic face of inside-out patches from Xenopus oocytes injected with F1304C RNA dramatically disrupted fast inactivation and displayed voltage-dependent reaction kinetics that closely paralleled the steady state availability (hinfinity) curve. Based on this observation, the accessibility of cys1304 was used as a conformational marker to probe the position of the fast inactivation gate during the development of and the recovery from slow inactivation. We found that burial of cys1304 is not altered by the onset of slow inactivation, and that recovery of accessibility of cys1304 is not slowed after long (2-10 s) depolarizations. These results suggest that (a) fast and slow inactivation are structurally distinct processes that are not tightly coupled, (b) fast and slow inactivation are not mutually exclusive processes (i.e., sodium channels may be fast- and slow-inactivated simultaneously), and (c) after long depolarizations, recovery from fast inactivation precedes recovery from slow inactivation

Inactivation defects caused by myotonia-associated mutations in the sodium channel III-IV linker.

Missense mutations in the skeletal muscle Na+ channel alpha subunit occur in several heritable forms of myotonia and periodic paralysis. Distinct phenotypes arise from mutations at two sites within the III-IV cytoplasmic loop: myotonia without weakness due to substitutions at glycine 1306, and myotonia plus weakness caused by a mutation at threonine 1313. Heterologous expression in HEK cells showed that substitutions at either site disrupted inactivation, as reflected by slower inactivation rates, shifts in steady-state inactivation, and larger persistent Na+ currents. For T1313M, however, the changes were an order of magnitude larger than any of three substitutions at G1306, and recovery from inactivation was hastened as well. Model simulations demonstrate that these functional difference have distinct phenotypic consequences. In particular, a large persistent Na+ current predisposes to paralysis due to depolarization-induced block of action potential generation

Guidelines on clinical presentation and management of non-dystrophic myotonias

The non‐dystrophic myotonias (NDMs) are rare muscle hyperexcitability disorders caused by gain‐of‐function mutations in the SCN4A gene or loss‐of‐function mutations in the CLCN1 gene. Clinically, they are characterized by myotonia, defined as delayed muscle relaxation after voluntary contraction, which leads to symptoms of muscle stiffness, pain, fatigue, and weakness. Diagnosis is based on history and examination findings, the presence of electrical myotonia on electromyography (EMG), and genetic confirmation. In the absence of genetic confirmation, the diagnosis is supported by detailed electrophysiological testing, exclusion of other related disorders, and analysis of a variant of uncertain significance (VUS) if present. Symptomatic treatment with a sodium channel blocker, such as mexiletine, is usually the first step in management, as well as educating patients about potential anesthetic complications

Hypokalemic Periodic Paralysis: a case report and review of the literature

Hypokalemic Periodic Paralysis is one form of Periodic Paralysis, a rare group of disorders that can cause of sudden onset weakness. A case of a 29 year old male is presented here. The patient presented with sudden onset paralysis of his extremities. Laboratory evaluation revealed a markedly low potassium level. The patient's paralysis resolved upon repletion of his low potassium and he was discharged with no neurologic deficits. An association with thyroid disease is well established and further workup revealed Grave's disease in this patient. Although rare, Periodic Paralysis must differentiated from other causes of weakness and paralysis so that the proper treatment can be initiated quickly

Myasthenic congenital myopathy from recessive mutations at a single residue in NaV1.4

OBJECTIVE: To identify the genetic and physiologic basis for recessive myasthenic congenital myopathy in 2 families, suggestive of a channelopathy involving the sodium channel gene, SCN4A. METHODS: A combination of whole exome sequencing and targeted mutation analysis, followed by voltage-clamp studies of mutant sodium channels expressed in fibroblasts (HEK cells) and Xenopus oocytes. RESULTS: Missense mutations of the same residue in the skeletal muscle sodium channel, R1460 of NaV1.4, were identified in a family and a single patient of Finnish origin (p.R1460Q) and a proband in the United States (p.R1460W). Congenital hypotonia, breathing difficulties, bulbar weakness, and fatigability had recessive inheritance (homozygous p.R1460W or compound heterozygous p.R1460Q and p.R1059X), whereas carriers were either asymptomatic (p.R1460W) or had myotonia (p.R1460Q). Sodium currents conducted by mutant channels showed unusual mixed defects with both loss-of-function (reduced amplitude, hyperpolarized shift of inactivation) and gain-of-function (slower entry and faster recovery from inactivation) changes. CONCLUSIONS: Novel mutations in families with myasthenic congenital myopathy have been identified at p.R1460 of the sodium channel. Recessive inheritance, with experimentally established loss-of-function, is a consistent feature of sodium channel based myasthenia, whereas the mixed gain of function for p.R1460 may also cause susceptibility to myotonia

Evidence for a heritable predisposition to Chronic Fatigue Syndrome

<p>Abstract</p> <p>Background</p> <p>Chronic Fatigue Syndrome (CFS) came to attention in the 1980s, but initial investigations did not find organic causes. Now decades later, the etiology of CFS has yet to be understood, and the role of genetic predisposition in CFS remains controversial. Recent reports of CFS association with the retrovirus xenotropic murine leukemic virus-related virus (XMRV) or other murine leukemia related retroviruses (MLV) might also suggest underlying genetic implications within the host immune system.</p> <p>Methods</p> <p>We present analyses of familial clustering of CFS in a computerized genealogical resource linking multiple generations of genealogy data with medical diagnosis data of a large Utah health care system. We compare pair-wise relatedness among cases to expected relatedness in the Utah population, and we estimate risk for CFS for first, second, and third degree relatives of CFS cases.</p> <p>Results</p> <p>We observed significant excess relatedness of CFS cases compared to that expected in this population. Significant excess relatedness was observed for both close (p <0.001) and distant relationships (p = 0.010). We also observed significant excess CFS relative risk among first (2.70, 95% CI: 1.56-4.66), second (2.34, 95% CI: 1.31-4.19), and third degree relatives (1.93, 95% CI: 1.21-3.07).</p> <p>Conclusions</p> <p>These analyses provide strong support for a heritable contribution to predisposition to Chronic Fatigue Syndrome. A population of high-risk CFS pedigrees has been identified, the study of which may provide additional understanding.</p

Star forming dwarf galaxies

Star forming dwarf galaxies (SFDGs) have a high gas content and low metallicities, reminiscent of the basic entities in hierarchical galaxy formation scenarios. In the young universe they probably also played a major role in the cosmic reionization. Their abundant presence in the local volume and their youthful character make them ideal objects for detailed studies of the initial stellar mass function (IMF), fundamental star formation processes and its feedback to the interstellar medium. Occasionally we witness SFDGs involved in extreme starbursts, giving rise to strongly elevated production of super star clusters and global superwinds, mechanisms yet to be explored in more detail. SFDGs is the initial state of all dwarf galaxies and the relation to the environment provides us with a key to how different types of dwarf galaxies are emerging. In this review we will put the emphasis on the exotic starburst phase, as it seems less important for present day galaxy evolution but perhaps fundamental in the initial phase of galaxy formation.Comment: To appear in JENAM Symposium "Dwarf Galaxies: Keys to Galaxy Formation and Evolution", P. Papaderos, G. Hensler, S. Recchi (eds.). Lisbon, September 2010, Springer Verlag, in pres

Groundwater Nitrogen Pollution and Assessment of Its Health Risks: A Case Study of a Typical Village in Rural-Urban Continuum, China

Protecting groundwater from nitrogen contamination is an important public-health concern and a major national environmental issue in China. In this study, we monitored water quality in 29 wells from 2009 to 2010 in a village in Shanghai city, whick belong to typical rural-urban continuum in China. The total N and NO3-N exhibited seasonal changes, and there were large fluctuations in NH4-N in residential areas, but without significant seasonal patterns. NO2-N in the water was not stable, but was present at high levels. Total N and NO3-N were significantly lower in residential areas than in agricultural areas. The groundwater quality in most wells belonged to Class III and IV in the Chinese water standard, which defines water that is unsuitable for human consumption. Our health risk assessments showed that NO3-N posed the greatest carcinogenic risk, with risk values ranging from 19×10−6 to 80×10−6, which accounted for more than 90% of the total risk in the study area