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Ion Channel Function (ion + channel_function)
Selected AbstractsGenotype-dependent sensitivity of hepatitis C virus to inhibitors of the p7 ion channel,HEPATOLOGY, Issue 6 2008Stephen Griffin The hepatitis C virus (HCV) p7 protein plays a critical role during particle formation in cell culture and is required for virus replication in chimpanzees. The discovery that it displayed cation channel activity in vitro led to its classification within the "viroporin" family of virus-coded ion channel proteins, which includes the influenza A virus (IAV) M2 protein. Like M2, p7 was proposed as a potential target for much needed new HCV therapies, and this was supported by our finding that the M2 inhibitor, amantadine, blocked its activity in vitro. Since then, further compounds have been shown to inhibit p7 function but the relationship between inhibitory effects in vitro and efficacy against infectious virus is controversial. Here, we have sought to validate multiple p7 inhibitor compounds using a parallel approach combining the HCV infectious culture system and a rapid throughput in vitro assay for p7 function. We identify a genotype-dependent and subtype-dependent sensitivity of HCV to p7 inhibitors, in which results in cell culture largely mirror the sensitivity of recombinant protein in vitro; thus building separate sensitivity profiles for different p7 sequences. Inhibition of virus entry also occurred, suggesting that p7 may be a virion component. Second site effects on both cellular and viral processes were identified for several compounds in addition to their efficacy against p7 in vitro. Nevertheless, for some compounds antiviral effects were specific to a block of ion channel function. Conclusion: These data validate p7 inhibitors as prototype therapies for chronic HCV disease. (HEPATOLOGY 2008;48:1779-1790.) [source] Diabetic neuropathies: components of etiologyJOURNAL OF THE PERIPHERAL NERVOUS SYSTEM, Issue 2 2008David R. Tomlinson Abstract This review examines the putative role of glucose in the etiology of diabetic neuropathies. Excessive glucose generates several secondary metabolic anomalies , principally oxidative stress (via both the polyol pathway and glucoxidation) and non-enzymic glycation of macromolecules. The latter is also facilitated by glucoxidation. These metabolic deviations trigger cellular responses that are inappropriate to normal function. Principal among these are neurotrophic deficits and phosphorylation of mitogen-activated protein kinases (MAPK). Downstream of these events are aberrant ion channel function and disordered gene expression, leading to changes in cellular phenotype. This leads directly to disordered nerve conduction, a recognised early clinical sign, and indirectly, via as yet undisclosed links, to sensory loss and axonopathy. Recent work also links MAPK activation to the development of neuropathic pain. [source] Axonal excitability properties in hemifacial spasmMOVEMENT DISORDERS, Issue 9 2007Arun V. Krishnan PhD, FRACP Abstract Hemifacial spasm (HFS) is characterized by involuntary, irregular contractions of muscles innervated by the facial nerve. Whether the facial nerve has a relative predisposition for ectopic activity has not been clarified. Nerve excitability techniques, which provide information about membrane potential and axonal ion channel function, were initially measured in 12 control subjects looking for biophysical differences that may predispose the facial nerve to generate ectopic activity. In a second series of studies, facial nerve excitability was assessed in nine HFS patients. In both series, stimulus,response behavior, threshold electrotonus, a current threshold relationship, and the recovery of excitability following supramaximal stimulation were recorded following stimulation of the facial nerve. When compared to normative data from nerves in the upper and lower limbs, there was a relative "fanning-in" of threshold electrotonus, reduced superexcitability, and increased subexcitability in facial nerve studies from control subjects (P < 0.05), consistent with relative axonal depolarization. These findings may underlie the propensity for the facial nerve to develop ectopic impulse activity in motor axons. In the HFS patient study, there were no significant differences in distal facial nerve excitability properties from the affected side in HFS patients when compared either to the unaffected side or to normative facial nerve data. It is concluded that the impulse generator underlying HFS must consequently be sited more proximally and does not cause a generalized disturbance of motor axon excitability. © 2007 Movement Disorder Society [source] Ion channel remodeling in gastrointestinal inflammationNEUROGASTROENTEROLOGY & MOTILITY, Issue 10 2010H. I. Akbarali Abstract Background,Gastrointestinal inflammation significantly affects the electrical excitability of smooth muscle cells. Considerable progress over the last few years have been made to establish the mechanisms by which ion channel function is altered in the setting of gastrointestinal inflammation. Details have begun to emerge on the molecular basis by which ion channel function may be regulated in smooth muscle following inflammation. These include changes in protein and gene expression of the smooth muscle isoform of L-type Ca2+ channels and ATP-sensitive K+ channels. Recent attention has also focused on post-translational modifications as a primary means of altering ion channel function in the absence of changes in protein/gene expression. Protein phosphorylation of serine/theronine or tyrosine residues, cysteine thiol modifications, and tyrosine nitration are potential mechanisms affected by oxidative/nitrosative stress that alter the gating kinetics of ion channels. Collectively, these findings suggest that inflammation results in electrical remodeling of smooth muscle cells in addition to structural remodeling. Purpose,The purpose of this review is to synthesize our current understanding regarding molecular mechanisms that result in altered ion channel function during gastrointestinal inflammation and to address potential areas that can lead to targeted new therapies. [source] From molecules to motion: altering neuronal ion channel function can lead to changes in intestinal motilityNEUROGASTROENTEROLOGY & MOTILITY, Issue 5 2007D. S. Strong First page of article [source] SYMPOSIUM REVIEW: Lipid microdomains and the regulation of ion channel functionTHE JOURNAL OF PHYSIOLOGY, Issue 17 2010Caroline Dart Many types of ion channel localize to cholesterol and sphingolipid-enriched regions of the plasma membrane known as lipid microdomains or ,rafts'. The precise physiological role of these unique lipid microenvironments remains elusive due largely to difficulties associated with studying these potentially extremely small and dynamic domains. Nevertheless, increasing evidence suggests that membrane rafts regulate channel function in a number of different ways. Raft-enriched lipids such as cholesterol and sphingolipids exert effects on channel activity either through direct protein,lipid interactions or by influencing the physical properties of the bilayer. Rafts also appear to selectively recruit interacting signalling molecules to generate subcellular compartments that may be important for efficient and selective signal transduction. Direct interaction with raft-associated scaffold proteins such as caveolin can also influence channel function by altering gating kinetics or by affecting trafficking and surface expression. Selective association of ion channels with specific lipid microenvironments within the membrane is thus likely to be an important and fundamental regulatory aspect of channel physiology. This brief review highlights some of the existing evidence for raft modulation of channel function. [source] Role of redox state in modulation of ion channel function by fatty acids and phospholipidsBRITISH JOURNAL OF PHARMACOLOGY, Issue 4 2003Zhiguo Wang British Journal of Pharmacology (2003) 139, 681,683. doi:10.1038/sj.bjp.0705307 [source] | ||||||||||