Jaarboek no. 89. 2010/2011 - Koninklijke Maatschappij voor ...

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Natuurkundige voordrachten I Nieuwe reeks 89 Migraine: de ontrafeling van een complexe ziekte 116 Figure 1 Schematic topographic drawing of the CaV2.1 (α1A ) subunit of the P/Q-type voltagegated calcium channel encoded by the FHM1 gene CACNA1A. The protein consists of four repeating domains (I–IV), each containing six transmembrane helices (S1–S6). The approximate locations of mutations linked to FHM are indicated. Amino acid positions refer to GenBank accession number X99897. the results and their interpretation. In addition, single-channel measurements (which were so effective in revealing gain-of-function effects for FHM mutations, as discussed above) are technically very challenging to perform and analyze. To help overcome these factors, the mutation can be introduced into the orthologous gene in the mouse genome by homologous recombination (the so-called gene-targeting strategy, and more specifically the knockin strategy). The advantages of this approach are that the mutation is present in all relevant splice forms of the gene, and the mutant protein is expressed in the appropriate tissues, at the appropriate levels, at the appropriate developmental stages, and with its appropriate binding partners. This strategy was employed for the R192Q mutation, which neutralizes a positive charge in the first voltage sensor (see Fig. 1). In principle, one would predict this mutation to decrease voltage sensitivity. However, a detailed examination of the channel properties revealed a clear gain of function: despite being expressed at levels equivalent to wild-type channels, much larger currents were observed at negative voltages (at −30 mV, the current through mutant channels was bet- ter than three times that of wild-type channels); at positive voltages, mutant channels carried the same current as wild-type channels. Thus, the increased currents at negative voltages could be explained in full by a negative shift in activation for the mutant channels. This shift is consistent with similar effects observed for other FHM1 mutations. Consistent with the role of CaV2.1 channels in mediating transmitter release at the neuromuscular junction, the R192Q mutant mice exhibited increased transmission from motor neurons. This increase was reflected in both a higher frequency of miniature (spontaneous) endplate potentials and larger evoked endplate potentials, both of which showed a gene-dosage effect. Interestingly, the effect of the mutation on evoked endplate potentials was observed only when extracellular Ca2+ was reduced to subphysiological levels, suggesting a ceiling effect in physiological Ca2+ concentrations, and perhaps explaining why R192Q patients do not present with chronic neuromuscular deficits. As discussed in Section III, CSD is believed to be the physiological correlate of the migraine aura. The naturally occurring mouse Cacna1a mutants tot-
tering and leaner exhibit decreased susceptibility for CSD, manifesting as an increased threshold for inducing a CSD event. Functionally, these mutations convey clear electrophysiological loss-of-function effects to the channels. In contrast, in keeping with a gain-of-function effect in FHM1, the R192Q knockin mice exhibited a decreased threshold for inducing a CSD event. Together, these findings suggest a direct positive correlation between channel function and spreading depression: more Ca2+ influx leads to an increased susceptibility for spreading depression in the cortex. This may have clinical significance, as decreasing calcium channel activity to wild-type levels in the brain might help rescue the migraine brain. B. Na + /K + -ATPase α2 transporter (FHM2) To date, 45 mutations in the ATP1A2 gene have been linked to FHM (Fig. 2), and several have been studied functionally. In vitro assays revealed that mutant proteins have decreased transporter activity, ranging from no activity at all to decreased affinity for K + , Natuurkundige voordrachten I Nieuwe reeks 89 Migraine: de ontrafeling van een complexe ziekte Figure 2 Schematic topographic drawing of the α2 subunit of the Na + /K + -ATPase transporter encoded by the FHM2 gene ATP1A2. The protein contains 10 transmembrane helices (S1–S10). The approximate locations of mutations linked to FHM are indicated. Amino acid positions refer to GenBank accession number NM_000702. and/or decreased catalytic turnover. Thus, the mutation leads to reduced reuptake of K + and glutamate from the synaptic cleft into glial cells. Because the FHM2 mutations impair protein function, it is interesting to compare the FHM2 phenotype with that of mice lacking Atp1a2 expression. Two lines of knockout mice have been generated, and in both cases the mice die immediately at birth due to severe motor deficits and failing respiration. Examination of the developing embryos revealed neuronal loss in the amygdala and piriform cortex secondary to neural hyperactivity. Moreover, Atp1a2 knockout mice on a 129sv genetic background survive briefly (
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NATUURKUNDIGE VOORDR ACHTEN 2010 -
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ISBN 978 90-72644-23-7 Drukkerij Vi
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INHOUD Diligentiaprijs voor Scholie
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VERSLAG VAN DE KONINKLIJKE MAATSCHA
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Oprichting in 1793 Het Gezelschap t
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N.Th. Michaelis 1898-1904 Dr. E.H.
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ALFABETISCH REGISTER VAN DE VOORDRA
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Natuurkundige voordrachten I Nieuwe
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Elektriciteitopslag in batterijen m
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De vermogensdichtheid van een batte
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Figuur 3 Het effect dat vacatures (
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Schakelbare spiegels: een samenspel
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Applications Beside their purely fu
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hydrogen absorption properties of t
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Gammaflitsen: extreem nieuws uit de
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ster ontstaat. Het directe bewijs v
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Figuur 2 Als we voor alle 2704 gamm
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gammaflits kan miljarden jaren na h
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Genetica en genoomonderzoek naar ve
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zingen in de code aanwezig die aang
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omdat we beschikken over de gezondh
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Microreactortechnologie; de chemisc
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matografie, maar is zeer succesvol
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Figuur 5 De economische haalbaarhei
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qubit can now be described as follo
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games not only nicely demonstrates
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