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The amiloride sensitive asics dynaflyte 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. , 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.

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 asics fuzex 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 in neurons of the CNS asics gel contend 3 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.

Exposure of ASICs to an acidic pHe leads to rapid channel opening, followed by a asics gel cumulus slower entry into a non conducting desensitized state. This results in a transient current (Figure 3 B). In some ASIC subtypes, such as ASIC3 and some heteromeric ASICs, desensitization is not complete, and a small sustained current persists after the initial peak (Lingueglia et al. , 1997 ; Waldmann et al. , 1997a ; Yagi et al. , 2006 ). Desensitization can also occur without apparent channel opening (termed steady state desensitization in this case) during moderate lowering of the pH and can limit the availability of ASICs for opening. The pH dependence of these two processes, channel activation and steady state desensitization, is illustrated by the example of ASIC1a in Figure 3 C. The steady state desensitization occurs at pH 50 ) of ~6.5. These parameters determine the open probability of ASICs under given pH conditions. As shown in Table 1 , ASIC1a and ASIC3 are the most sensitive ASICs and are activated by acidification to pH values only slightly below pH 7. In contrast, ASIC2a needs much more acidic pH ( 3 C and Table 1 ).

The authors showed that this activation is due to a shift in the pH dependence of activation. Administration of this combination of lipids induced pain that was prevented by ASIC3 inhibitors in rats and reduced in ASIC3 knockout mice.As mentioned above, ASIC inhibition is currently not used clinically. The present compounds except for amiloride, which is clinically used as ENaC inhibitor (IC 50 = 100 200 nM), have been characterized in cell systems and in part also in animal models. An interesting recent review of ASIC pharmacology is provided by Baron and Lingueglia ( 2015 ). Amiloride has a low potency (EC 50 of 10 100 ¼M) and selectivity on ASIC peak currents and does not inhibit the sustained ASIC currents. Amiloride binds into the pore of ENaC and ASICs (Schild et al. , 1997 ; Adams et al. , 1999 ; Alijevic and Kellenberger, 2012 ).

The activity of many neuronal ion channels is pH dependent (Table 3 ), suggesting that the pHe changes during neuronal activity modulate ion channel asics gel kayano evo 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 kayano evo-532whk.jpg[/img] principal sensors of rapid extracellular acidification in the brain.