Endogenous Neuropeptide Nocistatin Is a Direct Agonist of Acid-Sensing Ion Channels (ASIC1, ASIC2 and ASIC3)

Abstract

Acid-sensing ion channel (ASIC) channels belong to the family of ligand-gated ion channels known as acid-sensing (proton-gated) ion channels. Only a few activators of ASICs are known. These are exogenous and endogenous molecules that cause a persistent, slowly desensitized current, different from an acid-induced current. Here we describe a novel endogenous agonist of ASICs—peptide nocistatin produced by neuronal cells and neutrophils as a part of prepronociceptin precursor protein. The rat nocistatin evoked currents in X. laevis oocytes expressing rat ASIC1a, ASIC1b, ASIC2a, and ASIC3 that were very similar in kinetic parameters to the proton-gated response. Detailed characterization of nocistatin action on rASIC1a revealed a proton-like dose-dependence of activation, which was accompanied by a dose-dependent decrease in the sensitivity of the channel to the protons. The toxin mambalgin-2, antagonist of ASIC1a, inhibited nocistatin-induced current, therefore the close similarity of mechanisms for ASIC1a activation by peptide and protons could be suggested. Thus, nocistatin is the first endogenous direct agonist of ASICs. This data could give a key to understanding ASICs activation regulation in the nervous system and also could be used to develop new drugs to treat pathological processes associated with ASICs activation, such as neurodegeneration, inflammation, and pain.

Acid-sensing ion channel 3: An analgesic target

“…Interestingly, α-Dendrotoxin (α-DTx, Figure 8F), which comes from the eastern green mamba snake Dendroaspis angusticeps, inhibits acid-gated currents in DRG neurones (IC 50 of 0.8 µM, at pH 6.1) and although the currents were characteristic of ASIC3, this effect should be considered as non-selective ASIC inhibition before further characterisation of effects against ASIC3 in a recombinant expression system; there is also evidence that α-DTx inhibits voltage-gated K + channels (1.1, 1.2 and 1.6), thus the toxin has non-selective actions [206]. Lastly, the anti-nociceptive peptide nocistatin, which is produced by neuronal cells and neutrophils, has been shown to reduce the speed of activation (49%), amplitude (18%) and the rate of desensitisation (32%) of the rASIC3 transient current [211]. Therefore, it is possible that at least some of the anti-nociceptive effect of nocistatin is through inhibition of ASIC function.…”

“…Lastly, the anti-nociceptive peptide nocistatin, which is produced by neuronal cells and neutrophils, has been shown to reduce the speed of activation (49%), amplitude (18%) and the rate of desensitization (32%) of the rASIC3 transient current [ 211 ]. Therefore, it is possible that at least some of the anti-nociceptive effect of nocistatin is through inhibition of ASIC function.…”

Alkaloid Lindoldhamine Inhibits Acid-Sensing Ion Channel 1a and Reveals Anti-Inflammatory Properties

“…Endogenous neuropeptides dynorphins, RF-amide peptides, and endogenous cationic polyamine spermine potentiate ASIC1a’s response to acidification by inhibiting the desensitization of the channel, which leads to the neuronal damage in ischemic stroke models [11,12]. Endogenous opioid peptide nocistatin activates ASIC1a at physiological pH and decreases the sensitivity of the channel to the protons [13]. The snake toxin MitTx at nanomolar concentrations activates the ASIC1a channel and induces pain behavior [14].…”

Animal, Herb, and Microbial Toxins for Structural and Pharmacological Study of Acid-Sensing Ion Channels

“…ASIC2b and ASIC4 do not respond to the acid stimulus and apparently only form heteromeric channels with other isoforms, thereby influencing the function of the channel as a whole ( Deval et al., 2004 ; Donier et al., 2008 ; Sherwood et al., 2011 ). Under the action of an acid pulse, all functional ASICs form a rapidly activated current, which then desensitizes at different rates ( Figure 1A for ASIC1a subtype) ( Gründer and Pusch, 2015 ; Osmakov et al., 2019a ). According to the kinetics of desensitization, the currents of ASIC3 channels stand apart; in other words, a rapidly desensitizing (transient) component is followed by a non-desensitizing current (sustained component), which lasts as long as the stimulating pulse ( Figure 1B for ASIC3 subtype) ( Salinas et al., 2009 ; Osmakov et al., 2014 ).…”

“…Intensive studies of different ASIC modulators and knockout mice disclosed the role of these channels (at least ASIC1a and ASIC3) in detection of acidosis-mediated pain ( Rash and Rash, 2017 ). Several pro-inflammatory endogenous mediators affect ASICs function and potentiate their response to acidification (arachidonic acid and RF-amide peptides ( Askwith et al., 2000 ; Allen and Attwell, 2002 ), spermine, dynorphins, and histamine for ASIC1a ( Babini et al., 2002 ; Sherwood et al., 2009 ; Nagaeva et al., 2016 ), lactate and serotonin for ASIC3 ( Immke and McCleskey, 2001 ), and nocistatine and endogenous isoquinoline alkaloids ( Osmakov et al., 2017 ; Osmakov et al., 2019a ). Expression of ASIC1a in DRG neurons is elevated during inflammation and unregulated by inflammatory mediators ( Voilley et al., 2001 ; Mamet et al., 2002 ).…”