In spite of growing asics look evidence indicating that the density of ASICs is substantially higher in GABAergic interneurons than in glutamatergic cells [ 17 ] and recent demonstration of functional crosstalk between ASICs and GABA A -receptors [ 10 , 11 ], the possible involvement of ASICs in the regulation of GABAergic transmission remained unclear. In our work we present evidence for the first time that ASICs play a functional role at hippocampal GABAergic synapses. This role is mediated, at least partially, by a postsynaptic but (predominantly) modulatory mechanism.We found that GABAergic postsynaptic currents, recorded below their reversal potential as inward currents, are suppressed by all the employed blockers of ASICs.

Additionally, we would like to mention that although amioloride is known to be not selective at high concentrations (for instance [ 34 ]), at concentration (25 ¼M) used in asics shoes our experiments amiloride was shown to be a potent antagonist, mainly for ASIC receptors. As far as we know, diminazene is rather selective against ASICs within the time scale of our experiments (minutes). It does target DNA [ 35 ], but related consequences of this asics gel action shouldn't be expected within minutes. Indeed, we are not aware of any other than ASICs targets of diminazene, which could be responsible for  rapid' side effects.

Lack of substantial direct involvement of ASICs in PSCs generation in our experiments can be also supported by comparing the possible relative contribution of ASIC current to total synaptic current. Based on the results of our experiments with application of bicuculline alone, the relative contribution of ASIC currents to total synaptic current is less than 9 % (8.29 ± 2.24). Our experiments using 5b and suramin asics gel s suggest an even lower percentage. Indeed, the residual currents were nearly unaffected in presence of 5b (1 ¼M) but strongly suppressed (to 16.9 ± 4.3 % of control) by suramin at 200 ¼M concentration.

Since the density of proton-activated currents (evoked by pH shift to 5) is ~ 75 pA/pF in amygdala and 20 pA/pF in hippocampus [ 8 ], a much reduced proton-mediated component of synaptic current in the hippocampus may be expected. In our experiments, however, the absolute value of inward synaptic current suppressed by ASIC antagonists is about 40 60 pA. As for the current mediated by ASICs in hippocampal GABAergic synapses, we believe this was undetectable due to its small absolute and relative amplitude.Functional interaction between ASICs and GABA A -receptors in isolated neurons has been recently demonstrated [ 10 , 11 ].

ASICs are abundant in many brain areas and are known to have important physiological functions. However, because of rapid desensitization of ASIC-mediated currents, synapses are among the few places where they can be activated under physiological conditions and, thus, mediate asics gel kayano their physiological roles. In this work we demonstrated for the first time that three structurally different ASIC blockers affect GABAergic PSCS in a similar manner, strongly suggesting that ASICs are involved in regulation of GABAegic synaptic transmission under physiological conditions.

Considering our results and previously published data, we conclude that the effect of the ASIC blockers on GABAegic synaptic transmission is due to an at least partially postsynaptic but (predominantly) modulatory mechanism. Our results may be of importance for applied pharmacology, because ASICs are considered as therapeutic targets for neurological diseases and ASIC blockers as potential neuroprotectors [ 40 ].