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5b (novel blocker of ASICs) has little effect on asics look inward GABAergic currents in  HEPES 10' solution. In the same series of experiments during each sweep evoked PSCs were recorded below their reversal potential as inward currents ( a ), and above the reversal potential, as outward ones ( b ). Superimposed traces of original current traces (averages of 10 sequential PSCs) before (solid lines) and after (dotted lines) 5b (1 ¼M) application are shown on the right panel, summary graphs ( n = 5) are shown on the left panel. PSC-amplitudes were normalized to control values (average of 20 PSCs preceding drug application).

In control, absolute amplitudes of inward and outward currents (mean ± S.D) in asics shoes this series of experiments were: -196.3 ± 92.6 pA; 193.1 ± 119.6 pAA non-selective blocker of ASICs amiloride suppresses inward GABAergic currents. In the same series of experiments during each sweep evoked PSCs (2 PSCSs with 100 ms interval) asics gel were recorded below their reversal potential as inward currents ( a ), and above the reversal potential, as outward ones ( b ), see Methods for details. Superimposed traces of original current traces (averages of 10 sequential PSCs) before (solid lines) and after (dotted lines) amiloride (25 ¼M) application are shown on the right panel, summary graphs ( n = 5) are shown on the left panel.

In the same cells the suppression of postsynaptic currents, recorded above asics gel s their reversal potential as outward currents was statistically insignificant.Apart from the chemical dissimilarity of amiloride and diminazene, they are structurally different [ 24 ], and mechanisms of their action on ASICs are different as well [ 24 ]. Similarly, amiloride and 5b have different mechanisms of action on ASICs [ 21 ]. Indeed, 5b is an orthosteric antagonist of ASIC1 [ 21 ] while amiloride is an open channel blocker [ 33 ].

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 rather selective against ASICs within the time scale of our experiments asics gel kayano (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  rapid' side effects.

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 ].