ÿþAs mentioned above, ASIC inhibition is currently not used clinically. converse white 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 ).

Several antiprotozoal diarylamidines inhibit ASICs with IC 50 values of 0.3 38 ¼M (Chen et al.2010 ). A recent screening of a fragment library followed by converse black optimization led to ASIC3 inhibiting 2 aminopyridine derivatives with an IC 50 of ~3 ¼M (Wolkenberg et al.2011 ).Venom toxins acting on ASICs have been used to elucidate some of the physiological and pathological roles of ASICs (Wemmie et al.2013 ). In addition, complexes converse high tops of ASIC1 with toxins were used to determine the crystal structure of ASIC1 in the likely open conformation.

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. ASIC1a,  2a and  2b are converse black high tops widely expressed in the CNS (reiewed in Wemmie et al.2013 ; Kellenberger and Schild, 2015 ).

A recent study with rats suggests a species difference with regard to the role of ASICs in the fear circuitry. This study showed that ASIC1a activation reduces anxiety in rats, by enhancing inhibition in the basolateral amygdala (Pidoplichko et al.2014 ). The reason for this opposite role of ASICs in fear behaviour of mice and rats is currently not understood, and the rat data rely so far on one single study. Given the complexity of the expression and role of ASIC1a in the mouse fear circuitry (Chiang et al.2015 ), it seems plausible that the ASIC expression pattern in the fear circuitry may be different between mice and rats. The role of ASICs in fear expressions of humans is currently not known.

Several studies have shown that ASICs interact functionally with glutamate receptors in synaptic signalling and that a converse trainers functional ASIC is required for LTP, as discussed above (Wemmie et al.2002 ; Du et al.2014 ; Kreple et al.2014 ; Quintana et al.2015 ; Liu et al.2016 ). The initial LTP study in hippocampus suggested that activation of postsynaptic ASICs removes the Mg 2 block of NMDA receptors, because LTP was only disrupted in ASIC1a ("/") mice in physiological extracellular Mg 2 concentrations, but was normal at low Mg 2 concentrations (Wemmie et al.2002 ). This does not, however, explain the more recent observations in the amygdala, the nucleus accumbens and in accumbens and in hippocampal cultures after oxygen glucose deprivation.