Different modes of inhibition by adamantane amine derivatives and natural polyamines of the functionally reconstituted influenza virus M2 proton channel protein.

Lin, Tse-I; Hutter, Harald; Schroeder, Cornelia

doi:10.1099/0022-1317-78-4-767

Cited by 36 publications

(25 citation statements)

References 42 publications

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“…In HEK293 cells the activity of the channel produces changes in [K ϩ ] in that mimic inactivation and results in apparent changes in ion selectivity. By using the peak value of V rev and the pH in measured at the time of peak V rev , the permeability of H ϩ relative to that of Na ϩ was found to be about 1.5-2.0 ϫ 10 6 , consistent with the values found by Chizhmakov and co-workers (5) and consistent with results from reconstituted M 2 protein in vesicles (35,36). For CV-1 cells studied in the absence of Cl Ϫ and K ϩ ions and two oocytes studied in control solution, the measured values of V rev and the calculated values of E Hϩ were within a few mV, consistent with a high proton permeability.…”

Section: Fig 8 Effects Of Fccp On Oocytessupporting

confidence: 89%

Permeation and Activation of the M2 Ion Channel of Influenza A Virus

Mould¹,

Drury²,

Frings³

et al. 2000

Journal of Biological Chemistry

151

166

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The M 2 ion channel protein of influenza A virus is essential for mediating protein-protein dissociation during the virus uncoating process that occurs when the virus is in the acidic environment of the lumen of the secondary endosome. The difficulty of determining the ion selectivity of this minimalistic ion channel is due in part to the fact that the channel activity is so great that it causes local acidification in the expressing cells and a consequent alteration of reversal voltage, V rev . We have confirmed the high proton selectivity of the channel (1.5-2.0 ؋ 10 6 ) in both oocytes and mammalian cells by using four methods as follows: 1) comparison of V rev with proton equilibrium potential; 2) measurement of pH in and V rev while Na The M 2 protein of influenza A virus is thought to function as an ion channel that permits protons to enter virus particles during virion uncoating in endosomes. In addition, in influenza virus-infected cells, the M 2 protein causes the equilibration of pH between the acidic lumen of the trans-Golgi network and the cytoplasm (reviewed in Refs. 1 and 2). The activity of the M 2 ion channel is inhibited by the antiviral drug amantadine (3-5). The mature M 2 protein consists of a 23-residue N-terminal extracellular domain, a single internal hydrophobic domain of 19 residues that acts as a transmembrane domain and forms the pore of the channel, and a 54-residue cytoplasmic tail (6). Chemical cross-linking studies showed the M 2 protein to exist minimally as a homotetramer (7-9). Statistical analysis of the ion channel activity of mixed oligomers also indicated that a homotetramer is the minimal active oligomeric form of the protein (10).Despite the small size of the active M 2 oligomer, several lines of evidence indicate that ion channel activity is intrinsic to the M 2 protein. First, ion channel activity has been observed in three different expression systems, Xenopus oocytes (3, 11, 12), mammalian cells (5, 13), and yeast (14). Second, M 2 channel activity has also been recorded in artificial lipid bilayers from a reconstituted peptide corresponding to the transmembrane domain of the M 2 protein (15) and from purified M 2 protein (16). Thus, due to its structural simplicity, the M 2 ion channel is a potentially useful model for the study of ion channels in general.Although a great deal of evidence indicates H ϩ is the biologically relevant ion for the role of M 2 protein in the life cycle of the influenza virus (1, 3, 17-22), other ions have been shown to be capable of flowing through the channel (12). In addition, the ion selectivity measured for the M 2 channel has been found to differ depending on whether the activity was measured in Xenopus oocytes or mammalian cells. When M 2 protein was expressed in oocytes, V rev was found to differ from the proton equilibrium potential, E Hϩ as [H ϩ ] out was varied (12). On the other hand, when M 2 protein was expressed in MEL cells, V rev was found to agree with E Hϩ (5). In a recent study (23), we found I Hϩ of the M 2 ion channel to...

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Section: Fig 8 Effects Of Fccp On Oocytessupporting

confidence: 89%

Permeation and Activation of the M2 Ion Channel of Influenza A Virus

Mould¹,

Drury²,

Frings³

et al. 2000

Journal of Biological Chemistry

151

166

View full text Add to dashboard Cite

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“…Often other proteins or compounds influence the assembly and/or function of K + channels, and PBCV-1 encodes several proteins that could mediate these processes: (a) Potassium ion channel activity is often modulated by phosphorylation and dephosphorylation (102) (43,106,109). PBCV-1 encodes at least four enzymes associated with polyamine biosynthesis ( Figure 2C).…”

Section: Ion Channel Proteinsmentioning

confidence: 99%

Unusual Life Style of Giant Chlorella Viruses

Etten

2003

Annu. Rev. Genet.

175

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Paramecium bursaria chlorella virus (PBCV-1) is the prototype of a family of large, icosahedral, plaque-forming, dsDNA viruses that replicate in certain unicellular, eukaryotic chlorella-like green algae. Its 330-kb genome contains ~373 protein-encoding genes and 11 tRNA genes. The predicted gene products of ~50% of these genes resemble proteins of known function, including many that are unexpected for a virus, e.g., ornithine decarboxylase, hyaluronan synthase, GDP-D-mannose 4,6 dehydratase, and a potassium ion channel protein. In addition to their large genome size, the chlorella viruses have other features that distinguish them from most viruses. These features include: (a) The viruses encode multiple DNA methyltransferases and DNA site-specific endonucleases. (b) The viruses encode at least some, if not all, of the enzymes required to glycosylate their proteins. (c) PBCV-1 has at least three types of introns, a self-splicing intron in a transcription factorlike gene, a spliceosomal processed intron in its DNA polymerase gene, and a small intron in one of its tRNA genes. (d) Many chlorella virus-encoded proteins are either the smallest or among the smallest proteins of their class. (e) Accumulating evidence indicates that the chlorella viruses have a very long evolutionary history.

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“…5. A replication inhibition of influenza A virus by blockage of M2 protein ion channel leading to disturbed virus encoating and disturbed pH regulation (Takeda et al, 2002;Lin et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

Modulation of Human Motor Cortex Excitability by Single Doses of Amantadine

Reis

John

Heimeroth

et al. 2006

Neuropsychopharmacol

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Amantadine-sulfate has been used for several decades to treat acute influenza A, Parkinson's disease (PD), and acute or chronic druginduced dyskinesia. Several mechanisms of actions detected in vivo/in vitro including N-methyl-D-aspartate (NMDA)-receptor antagonism, blockage of potassium channels, dopamine receptor agonism, enhancement of noradrenergic release, and anticholinergic effects have been described. We used transcranial magnetic stimulation (TMS) to evaluate the effect of single doses of amantadine on human motor cortex excitability in normal subjects. Using a double-blind, placebo-controlled, crossover study design, motor thresholds, recruitment curves, cortical stimulation-induced silent period (CSP), short intracortical inhibition (ICI), intracortical facilitation (ICF), and late inhibition (L-ICI) in 14 healthy subjects were investigated after oral doses of 50 and 100 mg amantadine with single and paired pulse TMS paradigms. Spinal cord excitability was investigated by distal latencies and M-amplitudes of the abductor digiti minimi muscle. After intake of amantadine, a significant dose-dependent decrease of ICF was noticed as well as a significant increase of L-ICI as compared to placebo. The effect on ICF and L-ICI significantly correlated with amantadine serum levels. ICI was slightly increased after amantadine intake, but the effect failed to be significant. Furthermore, amantadine had no significant effects on motor thresholds, MEP recruitment curves, CSP, or peripheral excitability. In conclusion, a low dose of amantadine is sufficient in modulating human motor cortex excitability. The decrease of ICF and increase of L-ICI may reflect glutamatergic modulation or a polysynaptic interaction of glutamatergic and GABA-ergic circuits. Although amantadine has several mechanisms of action, the NMDA-receptor antagonism seems to be the most relevant effect on cortical excitability. As L-ICI can be influenced by this type of drug, it may be an interesting parameter for studies of motor learning and use-dependent plasticity.

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Different modes of inhibition by adamantane amine derivatives and natural polyamines of the functionally reconstituted influenza virus M2 proton channel protein.

Cited by 36 publications

References 42 publications

Permeation and Activation of the M2 Ion Channel of Influenza A Virus

Permeation and Activation of the M2 Ion Channel of Influenza A Virus

Unusual Life Style of Giant Chlorella Viruses

Modulation of Human Motor Cortex Excitability by Single Doses of Amantadine

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