PcTx1 inhibits mammalian ASIC1a converse white leather 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 of the other ASIC toxins are currently not known. Co crystallization showed that PcTx1 binds to the acidic pocket of ASIC1 and that the much larger Mit toxin binds to 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 ).

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 comme des garcons converse 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 ).

Localization by immunohistochemistry studies, evidence for the interaction with the postsynaptic converse all stars proteins PICK1 and AKAP150, and co localization with PSD 95 in spines together indicate that ASIC1a has a somatodendritic distribution (Zha, 2013 ) and is well situated for the detection of rapid synaptic pH changes. Several recent studies expressed light activated proton pumps in neurons or astrocytes. Light induced activation of these pumps led to extracellular acidification and ASIC activation (Li et al.2014 ; Zeng et al.2015 ; Ferenczi et al.2016 ).

The study by Chiang et al. investigated LTP at various synapses of amygdala neurons and found that the extent of LTP at different synapses correlated with the ASIC current density in postsynaptic neurons. off white converse Cell type specific deletion of ASIC1a showed that ASIC dependent LTP is required at several amygdala synapses for fear learning. ASIC4 does not form functional channels but is known to down regulate the expression of other ASIC subunits (Donier et al.2008 ). ASIC1a expression is therefore expected to be up regulated in ASIC4 "/" mice, and it was indeed shown that ASIC4 knockout mice have an increased freezing response (Lin et al.2015 ).

In the amygdala, the absence of ASIC1a decreased the EPSC amplitude only slightly, but markedly impaired the LTP (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 ).

Quintana et al. have shown that apart from influencing NMDA receptors, ASIC1a can induce a special form of LTP in the ischaemic converse cdg hippocampus via AMPA receptors (Quintana et al.2015 ). The AMPA receptors show a high degree of post ischaemic plasticity that contributes to the excitotoxicity in the CA1 region by two mechanisms, anoxic LTP during the first hours, and an increased expression of Ca 2  permeable AMPA receptor types several hours later (Pellegrini Giampietro et al.1992 ; Hsu and Huang, 1997 ). After an oxygen glucose deprivation, anoxic LTP was observed in organotypic hippocampal slice cultures of WT mice, but was absent in slice cultures of ASIC1a ("/") mice or after pharmacological blockade of ASIC1a (Quintana et al.2015 ).