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 Geplaatst: 01-07-2020 09:32:28 Onderwerp: asics netball shoes |
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The amiloride sensitive epithelial sodium channel (ENaC)/degenerin (DEG) superfamily asics nimbus of ion channels includes, besides ENaC and acid sensing ion channels (ASICs), the DEGs that are part of mechanotransduction complexes in C. elegans (Arnadottir et al. , 2011 ), the peptide gated channel Phe Met Arg Phe amide (FMRFa) activated Na channel (FaNaC) of snails (Lingueglia et al. , 2006 ), the mammalian bile acid sensitive ion channel (BASIC) (Wiemuth et al. , 2014 ) and Drosophila ENaC/DEG channels such as pickpocket, ripped pocket and others (Adams et al. , 1998 ) (Figure 1 A). Amino acid sequence identity between different ENaC/DEG subfamilies is 15 20%.Relations and roles of ENaC and ASICs. (A) Phylogenetic tree of the ENaC/degenerin (DEG) family, showing besides ASIC and ENaC the subfamilies pickpocket (PPK), degenerin, the FMRFa activated channel FaNaC and the BASIC (also known as hINaC or BLINaC). (B) Illustration of the different physiological and pathological roles of ASICs and ENaC.
ASICs and FaNaC are expressed in the nervous system, DEGs are present in touch sensitive neurons, BASIC shows highest expression in the brain, liver and intestine, and ENaC is found at highest levels in tight epithelia, while members of the Drosophila ENaC/DEG are probably expressed in many different tissues. FaNaC is an excitatory ion channel of the nervous system of snails, DEGs are critical for C. elegans asics kayano 23 touch sensation, and members of the Drosophila ENaC/DEG may also be involved in touch sensation, among other roles. BASIC is activated by bile acids; however, its physiological role is currently not known. ASICs are involved in fear behaviours, learning and memory functions, and pain sensation (Figure 1 B). They contribute to neurodegeneration after ischaemic stroke (reviewed in (Wemmie et al. , 2013 ; Kellenberger and Schild, 2015 ).
Models of ENaC subunits have asics running shoes been constructed based on the ASIC crystal structures. The highest homology of the ectodomain between ASICs and ENaC is found in the palm and the ² ball (Kashlan and Kleyman, 2011 ; Kashlan et al. , 2011 ). The predicted secondary structures of most other ENaC domains match the ASIC structure moderately well except for the finger that has the lowest homology and contains a ~80 amino acid insertion in ENaC (Figure 2 C).Stoichiometry predictions of ENaC and ASIC that were based on functional and biochemical data indicated that these channels are tetramers (Firsov et al. , 1998 ; Kosari et al. , 1998 ; Anantharam and Palmer, 2007 ; van Bemmelen et al. , 2015 ). In contrast, all crystal structures describe ASIC as a trimer.
In a recent study, ASIC1a and ASIC2a containing fluorescently labelled subunits were expressed in Xenopus oocytes, and the number asics gel nimbus of bleaching steps of plasma membrane resident channels was counted to determine the subunit stoichiometry of these functional channels at the cell surface (Bartoi et al. , 2014 ). This analysis indicated that functional ASICs at the cell surface are trimers. Similarly, an earlier study using fluorescence ratio measurements had concluded that ENaC is a trimer (Staruschenko et al. , 2005 ). In conclusion, the available data strongly support a trimeric structure of ASICs. Most likely, the subunit stoichiometry is conserved within the ENaC/DEG family.ASIC1a, 2a and 2b are widely expressed in the CNS. ASIC4, for which no channel activity has yet been demonstrated, shows a more dispersed expression in the CNS (Lin et al. , 2015 ); all ASIC subunits except ASIC4 are found in the adult peripheral nervous system (PNS; reviewed in Wemmie et al. , 2013 ; Kellenberger and Schild, 2015 ). Because ASICs are Na selective ion channels, their activation is expected to induce a neuronal depolarization.
Some of them have a high affinity for selected targets (IC 50 of PcTx1 for ASIC1a: 0.4 13 nM, EC 50 of Mit toxin for ASIC1a: 9 nM; Baron et al. , 2013 ) and may be used in binding studies after labelling, as shown for PcTx1 (Salinas et al. , 2006 ). The ASIC toxins have so far not been shown to target other channels besides ASICs, with the exception of APETx2, which also inhibits some voltage gated Na channel isoforms (IC 50 in the range of nanomolar to low micromolar concentrations) (Blanchard et al. , 2012 ; Peigneur et al. , 2012 ). PcTx1 inhibits mammalian ASIC1a by an alkaline shift in the pH dependence of steady state desensitization (leading to complete desensitization at pH 7.4), while Mambalgin inhibition is due to an acidic shift in the pH dependence of activation. The mechanisms of action of the other ASIC toxins are currently not known.
The activity of many neuronal ion channels is pH dependent (Table 3 ), suggesting that the pHe changes during neuronal activity modulate ion channel asics netball shoes function. In general, alkaline pHe favours inward currents, thus enhancing excitability, while acidic pHe depresses excitability in many circumstances (Chesler, 2003 ) and can be considered as negative feedback because it is caused by neuronal stimulation. ASICs in contrast are activated by extracellular acidification. Administration of specific ASIC1a antagonists or disruption of the ASIC1a gene eliminates the majority of the acid induced currents in CNS neurons (Wemmie et al. , 2013 ; Wu et al. , 2013 ). This demonstrates that the ASIC1a homomers and ASIC1a containing heteromers are the [img]http://www.jeanwyllys.com/images/detail/asics gel nimbus-666afg.jpg[/img] principal sensors of rapid extracellular acidification in the brain. |
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