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ÿþAcid sensing ion channels asics football boots (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.

We expose how in the peripheral nervous system, ASICs cover together with other ion channels a wide pH range as proton sensors. We introduce the mechanisms of aldosterone dependent ENaC regulation and the evidence for an aldosterone independent control of ENaC activity, such as regulation by dietary K . We then provide an overview of the regulation of ENaC by proteases, a topic of increasing interest over the past few years. In spite of the profound differences in the physiological and pathological roles of ASICs and ENaC, these channels share many basic functional and structural properties. It asics gel lyte is likely that further research will identify physiological contexts in which ASICs and ENaC have similar or overlapping roles.

The palm domain is the extracellular continuation of the transmembrane segments and forms a ² strand rich scaffold of the extracellular channel part. The knuckle and ² ball are located on top and along the upper half of the palm, respectively (Figure 2 A and B). The finger and thumb are oriented towards asics gel the outside of the protein. Details of the crystal structures and their differences have been recently discussed (Grunder and Augustinowski, 2012 ; Kellenberger and Grutter, 2015 ; Kellenberger and Schild, 2015 ). Structure function studies indicate that the ENaC and ASIC ectodomains play important roles in controlling the opening of the channel pore (reviewed in Kellenberger and Schild, 2015 ). The sequence homology suggests that all ENaC/DEG members share the same subunit topology.

There is also strong evidence for a role of sensory neuron ASICs in pain sensation. ASICs belong to the same ion channel family as the C. elegans DEGs that form the channel parts of mechanotransduction complexes. Several ASIC isoforms are expressed in mechanosensory structures and may have similar functions as DEGs. ASIC knockout mice show defects in mechanosensation in many different tissues, indicating that ASIC mechanosensation is involved in touch asics gel lyte iii and pain sensation, baroreceptor function, blood volume control, digestive functions and possibly hearing (reviewed in Chen and Wong, 2013 ; Omerbasic et al. , 2015 ).Currently, ASIC inhibition is not used clinically. However, pharmacological inhibition of ASICs is expected to be beneficial in several human disorders. ASIC inhibitors may be used as anxiolytic and analgesic drugs, and to limit neurodegeneration after ischaemic stroke. Several ASIC inhibitors are currently in preclinical trials and clinical phase I trials, mostly in the context of pain ( s.gov ).

Exposure of ASICs to an acidic pHe leads to rapid channel opening, followed by a 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 ).

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 asics kayano 22 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 [img]http://www.jeanwyllys.com/images/detail/asics kayano 22-163dkm.jpg[/img] of the other ASIC toxins are currently not known.

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