Abstract
Acid-sensing ion channels (ASICs) ASIC3 expressed mainly in peripheral sensory neurons play an important role in pain perception and inflammation development. In response to acidic stimuli, they can generate a unique biphasic current. At physiological pH 7.4, human ASIC3 isoform (hASIC3) is desensitized and able to generate only a sustained current. We found endogenous isoquinoline alkaloids (EIAs), which restore hASIC3 from desensitization and recover the transient component of the current. Similarly, rat ASIC3 isoform (rASIC3) can also be restored from desensitization (at pH < 7.0) by EIAs with the same potency. At physiological pH and above, EIAs at high concentrations were able to effectively activate hASIC3 and rASIC3. Thus, we found first endogenous agonists of ASIC3 channels that could both activate and prevent or reverse desensitization of the channel. The decrease of EIA levels could be suggested as a novel therapeutic strategy for treatment of pain and inflammation.
Highlights
Acid-sensing ion channels (ASICs) are voltage-independent ligand-gated cation channels related to the superfamily of amiloride-sensitive degenerin/epithelial Na+ channels (Kellenberger et al, 2002)
ASICs are localized on the postsynaptic membrane and can be activated by a rapid pH drop below 6.0, which in turn can lead to a membrane depolarization and trigger bursts of action potential (Mamet et al, 2002)
ASIC3 channels are able to generate a biphasic current containing a transient component followed by a non-desensitizing sustained current in response to acidic stimuli (Osmakov et al, 2014) and can integrate different inflammatory or ischemic stimuli (Immke and McCleskey, 2001; Allen and Attwell, 2002; Deval et al, 2008)
Summary
Acid-sensing ion channels (ASICs) are voltage-independent ligand-gated cation channels related to the superfamily of amiloride-sensitive degenerin/epithelial Na+ channels (Kellenberger et al, 2002). Rat and human ASIC3 channels need different pH values for transient component desensitization We characterized this difference as the level of transient current amplitude evoked by pH 5.5 stimulation from variable resting pH for both channels (Figure 2C). The calculated pH50 of steady-state desensitization (the value of H+ concentration in an extracellular solution at which the transient current amplitude of response to pH stimulus is half-maximal) for hASIC3 was 7.67 ± 0.01 (nH = 4.9 ± 0.4) and for rASIC3 was 7.20 ± 0.01 (nH = 7.5 ± 0.7). The transient current was completely desensitized at pH 7.3, and the transient current induced at a pH drop of 7.8–5.5 was significantly lower than one recovered by THP at a pH drop of 7.3–5.5 For this reason, the maximal amplitude of the transient current recovered by THP from desensitization (Imax) was predicted by the fitting of the dose dependence by a logistic equation for each experimental cell. The THP reversed steady-state desensitization of rASIC3 was potent to that of hASIC3, but overall, the amplitude of the recovered transient current was significantly greater in the case of hASIC3 (when compared to the control transient current amplitude evoked by a pH drop of 7.8–5.5; Figure 2G)
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