In spite converse look of the fact that the first evidence indicating the presence of receptor for protons in the nerve cell membrane was obtained a long time ago [ 28 ] and tremendous progress in this field has been demonstrated in the subsequent studies [ 5 , 9 , 16 , 29  32 ] the physiological role of ASICs is still far from being clear. Their involvement in regulation and plasticity of glutamatergic synaptic transmission in the hippocampus has been demonstrated. Protons are considered to be neurotransmitters regulating synaptic plasticity in the lateral amygdala [ 5 ].

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 our experiments amiloride was shown to be a potent antagonist, mainly for ASIC receptors. As far as we know, diminazene is converse all star rather selective against ASICs within the time scale of our experiments (minutes). It does target DNA [ 35 ], but related consequences of this 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 converse all stars  rapid' side effects.

Since suramin (500 ¼M) does not affect ASIC currents in hippocampal neurons [ 24 ] the above results also indicate that relative contribution of  synaptic' ASIC current is much smaller than 9 %. At the same time, the relative magnitude of the effects produced by ASIC blockers on synaptic currents recorded in the absence of bicuculline is about 20-30 %. These results, taken together, strongly support our point that the suppressing effect of the ASICs blockers on GABAergic transmission is due, predominantly to a modulatory mechanism. Additionally, we would like to mention that absolute amplitude of proton-mediated converse off white synaptic currents in amygdala is about 7-10 pA [ 5 ].

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 ].

This suggestion is also indirectly supported by the observation that modulatory effect of GABA A -receptors activation on ASICs-currents can be observed in excised patches [ 10 ]. We assume that an interaction between ASICs and GABA A -receptors is quite likely to occur at GABAergic synapses upon acidification at the synaptic cleft. This assumption can be supported by the lack of the apparent effect of 5b on inward PSCS in the presence of bicuculline, observed in our off white converse experiments.

It is worth noting that feature of voltage-dependence of interaction between receptors is, of itself, not very surprising. Indeed, a physical link between group-I metabotropic glutamate receptors and NMDA receptors results in a functional crosstalk, which is voltage-dependent [ 39 ]. Nevertheless we cannot currently exclude a possibility that the modulation of PSCs by ASICs under our experimental conditions depends on the direction of the current, rather than being intrinsically voltage-dependent. This, however, is less likely because in isolated neurons the interaction of ASICs and GABAA receptors does not depend on the direction of the GABA-current [ 10 ].