12/13/2019
Barlow Pritt
Posts: 4
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The most important ASIC toxins are the gating modifiers PcTx1 converse white of the spider Psalmopoeus cambridgei and the Mambalgins of the black mamba, the ASIC3 inhibitor APETx2 of the sea anemone Anthopleura elegantissima and the activating Mit toxin of the Texas coral snake that generates a sustained ASIC opening at pH 7.4 (reviewed in Baron et al.2013 ). MIT toxin and Mambalgins target several ASIC subtypes, while PcTx1 is selective for ASIC1a homomers and ASIC1a/2b heteromers, and APETx2 for ASIC3 containing channels. IC 50 and EC 50 values of these toxins range from nanomolar to micromolar concentrations.
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 converse black 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 converse high tops was also found in nucleus accumbens (Kreple et al.2014 ).
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. 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 ). converse black high tops 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 ).
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.
Inhibition of ASIC1a converse trainers or of Ca 2 permeable AMPA receptors was sufficient to protect neurons of the CA1 area, illustrating the important role of ASICs in neurodegeneration in this context.In summary, pH changes occur in the CNS during neuronal and metabolic activity. The synaptic cleft is acidified upon presynaptic stimulation, leading to the activation of postsynaptic ASICs. In spite of their small contribution to the postsynaptic currents, ASICs play a critical role in synaptic signalling.Nociceptive fibres conduct signals from the periphery to the CNS that are induced by a variety of potential  tissue damaging stimuli such as heat, pressure and chemicals.
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