TVC 't Hoekske

TimAbe · Newbie Geregistreerd op: 22 Jun 2020 Berichten: 6

ÿþAcid sensing ion channels (ASICs) and the epithelial Na asics football boots 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.

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 asics gel lyte 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 asics gel 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 ).

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 asics gel lyte iii 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 ).

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 kayano 22 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 kayano 22-163dkm.jpg[/img] principal sensors of rapid extracellular acidification in the brain.