Abstract
Currently, five peptide modulators of acid-sensing ion channels (ASICs) attributed to structural class 1b of sea anemone toxins have been described. The APETx2 toxin is the first and most potent ASIC3 inhibitor, so its homologs from sea anemones are known as the APETx-like peptides. We have discovered that two APETx-like peptides from the sea anemone Heteractis crispa, Hcr 1b-3 and Hcr 1b-4, demonstrate different effects on rASIC1a and rASIC3 currents. While Hcr 1b-3 inhibits both investigated ASIC subtypes with IC50 4.95 ± 0.19 μM for rASIC1a and 17 ± 5.8 μM for rASIC3, Hcr 1b-4 has been found to be the first potentiator of ASIC3, simultaneously inhibiting rASIC1a at similar concentrations: EC50 1.53 ± 0.07 μM and IC50 1.25 ± 0.04 μM. The closest homologs, APETx2, Hcr 1b-1, and Hcr 1b-2, previously demonstrated the ability to inhibit hASIC3 with IC50 63 nM, 5.5, and 15.9 μM, respectively, while Hcr 1b-2 also inhibited rASIC1a with IC50 4.8 ± 0.3 μM. Computer modeling allowed us to describe the peculiarities of Hcr 1b-2 and Hcr 1b-4 interfaces with the rASIC1a channel and the stabilization of the expanded acidic pocket resulting from peptides binding which traps the rASIC1a channel in the closed state.
Highlights
Acid-sensing ion channels (ASICs) activated by extracellular pH decrease are members of the amiloride-sensitive degenerin/epithelial sodium channels (DEG/ENaC) superfamily
We have investigated in depth the electrophysiological effects of two previously isolated peptides, Hcr 1b-3 and Hcr 1b-4, on homomeric rASIC1a and rASIC3 channels expressed in Xenopus laevis oocytes and found a fundamental distinction between their action modes
Among the great diversity of sea anemone peptide structures, the H. crispa toxins (HcrTxs) affecting channels should be attributed to the class 1b [26,27]
Summary
Acid-sensing ion channels (ASICs) activated by extracellular pH decrease are members of the amiloride-sensitive degenerin/epithelial sodium channels (DEG/ENaC) superfamily. Neuron damage was revealed to be associated with the activation of ASIC1a due to the prolonged acidosis resulting from pathological conditions (ischemic stroke, epilepsy, multiple sclerosis, Parkinson’s disease, etc.) [4,5,9]. This makes ASIC1a a promising target for neuroprotective interventions. It has been determined that the peculiarity of ASIC3 channels is their ability to generate sustained currents in addition to the conventional transient currents. This phenomenon defines the functional consequences of ASIC3 activation [3,4]
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