Complex action of tyramine, tryptamine and histamine on native and recombinant ASICs

Abstract

Proton-gated channels of the ASIC family are widely distributed in the mammalian brain, and, according to the recent data, participate in synaptic transmission. However, ASIC-mediated currents are small, and special efforts are required to detect them. This prompts the search for endogenous ASIC ligands, which can activate or potentiate these channels. A recent finding of the potentiating action of histamine on recombinant homomeric ASIC1a has directed attention to amine-containing compounds. In the present study, we have analyzed the action of histamine, tyramine, and tryptamine on native and recombinant ASICs. None of the compounds caused potentiation of native ASICs in hippocampal interneurons. Furthermore, when applied simultaneously with channel activation, they produced voltage-dependent inhibition. Experiments on recombinant ASIC1a and ASIC2a allowed for an interpretation of these findings. Histamine and tyramine were found to be inactive on the ASIC2a, while tryptamine demonstrated weak inhibition. However, they induce both voltage-dependent inhibition of open channels and voltage-independent potentiation of closed/desensitized channels on the ASIC1a. We suggest that the presence of an ASIC2a subunit in heteromeric native ASICs prevents potentiation but not inhibition. As a result, the inhibitory action of histamine, which is masked by a strong potentiating effect on the ASIC1a homomers, becomes pronounced in experiments with native ASICs.

Molecular mechanism and structural basis of small-molecule modulation of the gating of acid-sensing ion channel 1

“…Note the extended GAS belt conformation and TM2b domain swap in ΔASIC1/JNJ-799760. inhibition by PcTx1 16,34 ; compound 5b, a PcTx1-inspired small synthetic molecule that is modeled to bind in the acidic pocket, is an allosteric inhibitor of channel activation 28 ; Daurisoline and 2guanidine-4-methyl-quinazoline (GMQ, a non-proton agonist of ASIC3) both cause an acidic shift of the pH dependence of ASIC1a activation and desensitization 35,36 ; and histamine shifts the pH dependence of activation toward more basic pHs and of desensitization toward more acidic pHs 37,38 . However, these and other studies of small molecule modulation of ASIC1a to date have generally lacked substantive evidence necessary for elucidating the molecular and structural basis of modulation.…”

Trace Amines and Their Receptors

“…Such an effect suggests a TRP-mediated regulation of receptor-G protein coupling mechanisms. As indicated above, TRP has also been reported to regulate ASIC1a ion channels (Barygin et al, 2017) and to 564 promote the adherence of staphylococci species to gastrointestinal epithelial cells (Luqman et al, 2018).…”

“…As described above, such production promotes adherence of microbes to enterocytes (Fernández de Palencia et al, 2011;Luqman et al, 2018) and may modulate subsequent cytokine signaling by the enterocytes (Fernández de Palencia et al, 2011). TYR, along with TRP, has also recently been reported to regulate individual isoforms of neuronal acid-sensing ion channels (ASICs) (Barygin et al, 2017), an effect seen as a voltage-dependent inhibition of opening and a voltageindependent potentiation of closing of the ASIC1a isoform.…”

Ligands of Acid-Sensing Ion Channel 1a: Mechanisms of Action and Binding Sites

“…2 ). A similar effect was also established for tyramine and tryptamine, which did not shift the activation curve [66]. Even memantine, an inhibitor of open ASIC1a channels, exhibited potentiating activity when applied between channel activations at pH 7.1 (i.e., in the case of interaction with closed and desensitized channels only) [65].…”