ÿþAcid sensing ï»¿asics shoes ion channels (ASICs) and 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.
is also evidence for an involvement of ASICs in mechanosensation (Chen and Wong, 2013 ). ENaC plays a well established role in Na reabsorption in the distal nephron, distal colon and airway epithelia. In addition, it is involved in salt taste perception, epidermal differentiation and skin barrier function (Figure 1 B).Crystal structures of chicken ASIC1, which in some studies was co crystallized with the ASIC toxins psalmotoxin 1 (PcTx1) or MIT toxin, showed a channel made up of three subunits (Jasti et al. , asics kayano 2007 ; Gonzales et al. , 2009 ; Baconguis and Gouaux, 2012 ; Dawson et al. , 2012 ; Baconguis et al. , 2014 ). The shape of each subunit was compared with that of a hand holding a small ball, and accordingly, the different extracellular domains were labelled palm, knuckle, finger, thumb and ² ball (Figure 2 A).
Models of ENaC subunits have been constructed based asics gel kayano 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.
For several ASICs it has been shown that with fast solution asics gt 2000 changes the opening time constant at a pH that fully activates the channels is of the order of ~10 ms (Bassler et al. , 2001 ). The kinetics of current desensitization depend on the subunit composition, as shown in Table 1 . Besides protons, there are only very few ASIC activators known so far. The small synthetic molecule 2 guanidine 4 methylquinazoline (GMQ) activates ASIC3 at pH 7.4 and inhibits other ASIC subtypes by changing the pH dependence of activation and of steady state desensitization (EC 50 ~ 1 mM; Yu et al. , 2010 ; Alijevic and Kellenberger, 2012 ). Interestingly, endogenous arginine metabolites that contain a guanidinium group, as does GMQ, were found to have similar effects as GMQ (EC 50 > 3 mM; Li et al. , 2011 ). A recent study showed activation of ASIC3 at pH 7.4 by administration of the two lipids lysophosphatidylcholine (EC 50 ~ 4.3 ¼M) and arachidonic acid (used at 10 ¼M), which are both present in inflammatory exudates (Marra et al. , 2016 ).
In addition, complexes of ASIC1 with toxins were used to determine the crystal structure of ASIC1 in the likely open conformation. The most important ASIC toxins are the gating modifiers PcTx1 of the spider Psalmopoeus cambridgei and the Mambalgins of the black mamba, the ASIC3 inhibitor APETx2 of the sea anemone Anthopleura elegantissima and the activating Mit toxin of the Texas coral snake that generates a sustained ASIC opening at pH 7.4 (reviewed in Baron et al. , 2013 ). MIT toxin and Mambalgins target several ASIC subtypes, while PcTx1 is selective for ASIC1a homomers and ASIC1a/2b heteromers, and APETx2 for ASIC3 containing channels. IC 50 and EC 50 values of these toxins range from nanomolar to micromolar concentrations.
The activity of many neuronal ion channels is pH dependent (Table 3 ), suggesting that the pHe changes during neuronal activity modulate ion channel asics tiger 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 principal sensors of rapid extracellular acidification in the brain.