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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 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 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 ; asics gel lyte 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.

Indeed, activation of ASICs in neurons of the CNS and PNS induces membrane depolarization and generation of action potentials asics gel (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.

Recent studies have added important new information on the asics gel lyte iii role of ASICs in synaptic functions (see below). ASIC1a is highly expressed in the amygdala, and there is strong evidence that ASIC1a of 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 lowered in inflammation and ischaemia, which both involve pain.

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 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 ( ).

Co crystallization showed that PcTx1 binds to the acidic pocket of ASIC1 and that the much larger Mit toxin binds to asics kayano 22 the wrist, palm and thumb domains, without however reaching into the acidic pocket (Baconguis and Gouaux, 2012 ; Dawson et al. , 2012 ; Baconguis et al. , 2014 ). Site directed mutagenesis indicated that Mambalgins also bind to the acidic pocket (Salinas et al. , 2014 ; Schroeder et al. , 2014 ).In this section, we present the experimental evidence for a role of protons as a neurotransmitter. We discuss then how ASICs contribute to synaptic signalling and LTP, thereby affecting learning and fear sensation. Finally, we review different
observations, suggesting that ASICs can strongly influence glutamate receptor function.

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