ÿþAs mentioned above, ASIC asics trainers 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 site of action of other small molecule inhibitors on ASICs is not known. Amiloride derivatives modified at the five position of the pyrazine asics running shoes ring by hydrophobic groups increased the potency for ASIC3 inhibition by up to 100 fold (Kuduk et al.2009 ). Nafamostat mesylate, an anti inflammatory agent and protease inhibitor, contains a guanidinium moiety as do amiloride and GMQ and was shown to inhibit asics gel kayano ASIC currents, including the sustained current of ASIC3, with IC 50 values of 2 70 ¼M (Ugawa et al.2007 ). The chemically unrelated compound A 317 567 inhibits peak and sustained currents of neuronal and recombinant ASICs with IC 50 values between 2 and 30 ¼M (Dube et al.2005 ).

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 asics gt 2000 et al.2013 ). This demonstrates that the ASIC1a homomers and ASIC1a containing heteromers are the principal sensors of rapid extracellular acidification in the brain. ASIC1a,  2a and  2b are widely expressed in the CNS (reiewed in Wemmie et al.2013 ; Kellenberger and Schild, 2015 ).

In the lateral amygdala, presynaptic stimulation activated postsynaptic ASIC currents. Perfusion of glutamate receptor blockers inhibited 95% of the amplitude of the observed excitatory postsynaptic currents. The remaining 5% of the excitatory postsynaptic current amplitude were mediated by ASICs, because this current was absent in the presence of amiloride or if the ASIC1a gene was deleted (Du et al.2014 ). A similar situation with a contribution of ASICs to 5% of the excitatory postsynaptic current amplitude was also found in nucleus accumbens (Kreple et al.2014 ).

In the amygdala, the absence of ASIC1a decreased the EPSC amplitude only slightly, but markedly impaired the LTP asics netball trainers (Du et al.2014 ). Similarly, the presence or absence of ASIC1a strongly influenced glutamate receptor function in the nucleus accumbens (Kreple et al.2014 ). The mechanism of this functional interaction of ASIC1a with glutamate receptors is not understood. An earlier study had shown that during ischaemia, NMDA receptor activity leads to phosphorylation of ASIC1a by CaMKII that enhances ASIC currents and leads to ischaemic cell death (Gao et al.2005 ). There are also indications that the presence of ASICs can influence the density of dendritic spines and the glutamate receptor composition (Zha et al.2006 ; Kreple et al.2014 ).