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星期三 七月 08, 2020 4:28 pm
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SamCarl



註冊時間: 2020-07-08
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ÿþAcid sensing ion channels (ASICs) and asics football boots the epithelial Na channel (ENaC) are both members of the ENaC/degenerin family of amiloride sensitive Na channels. ASICs act as proton sensors in the nervous system where they contribute, besides other roles, to fear behaviour, learning and pain sensation. ENaC mediates Na reabsorption across epithelia of the distal kidney and colon and of the airways. ENaC is a clinically used drug target in the context of hypertension and cystic fibrosis, while ASIC is an interesting potential target. Following a brief introduction, here we will review selected aspects of ASIC and ENaC function. We discuss the origin and nature of pH changes in the brain and the involvement of ASICs in synaptic signalling.

The amiloride sensitive epithelial sodium channel (ENaC)/degenerin (DEG) superfamily 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. asics gel lyte , 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 gel Models of ENaC subunits have 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.

Indeed, activation of ASICs asics gel lyte iii in neurons of the CNS and PNS induces membrane depolarization and generation of action potentials (Figure 3 A) (Deval et al. , 2003 ; Vukicevic and Kellenberger, 2004 ; Poirot et al. , 2006 ). ASIC1a shows, in addition to its Na permeability, a small permeability for Ca 2 that is probably important for some of its roles (Waldmann et al. , 1997b ; Bassler et al. , 2001 ; Boillat et al. , 2014 ).Functional properties of ASIC. (A) Action potential induction by extracellular acidification to pH 6.4, mediated by ASICs, measured by whole cell current clamp from a mouse hippocampal neuron. (B) A pH 5 induced current recorded in whole cell voltage clamp to "60 mV from a Chinese hamster ovary cell stably transfected with ASIC1a. (C) The pH dependence of steady state desensitization and of activation of ASIC1a.

In steady state desensitization experiments, cells were exposed for 55 s to the indicated conditioning pH, and a stimulation pH 6 solution was applied for 5 s to open the not yet desensitized channels. The normalized current response at pH 6 is plotted as a function of the conditioning pH. For ASIC1a activation, the cells were perfused by a pH 7.4 solution, and once per minute, this solution was changed to one of acidic pH to open the channels. The normalized current is plotted as a function of the stimulation pH.Synaptic signalling involves an acidification of the synaptic cleft, which can activate ASICs. Disruption of the ASIC1a encoding gene in mice eliminated most of the ASIC currents of CNS neurons, impaired long term potentiation (LTP) in the hippocampus and induced a mild deficit in spatial learning (Wemmie et al. , 2002 ).

Recent studies have added important new information on the role of ASICs in synaptic functions (see below). ASIC1a is highly expressed in the amygdala, and there is strong evidence that ASIC1a of asics kayano 22 the amygdala contributes to fear behaviour (Wemmie et al. , 2013 ). Disruption of ASIC1a or inhibition of ASIC1a activity in the brain by PcTx1 containing venom reduced the infarct volume in an experimental stroke model by >50%, strongly suggesting that ASIC1a activation contributes to neurodegeneration in this situation (Xiong et al. , 2004 ). Further studies showed that disruption of ASIC1a had a protective effect in several neurodegenerative diseases, including multiple sclerosis, Huntington's and Parkinson's disease (reviewed in Wemmie et al. , 2013 ). The extracellular pH (pHe) is [img]http://www.jeanwyllys.com/images/detail/asics kayano 22-163dkm.jpg[/img] lowered in inflammation and ischaemia, which both involve pain.
 
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