Abstract
Acid-sensing ion channels (ASICs) belong to the degenerin/epithelial sodium channel protein family that form mechanosensitive ion channels. Evidence as to whether or not ASICs activity is directly modulated by mechanical force is lacking. Human ASICs (hASIC1V3, hASIC2a and hASIC3a) were heterologously expressed as homomeric channels in Xenopus oocytes and two-electrode voltage-clamp recordings were performed. hASIC3a was expressed in HEK-293 cells and currents measured by whole-cell patch-clamp recordings. ASIC currents in response to shear force (SF) were measured at pH 7.4, acidic pH, or in the presence of non-proton ligands at pH 7.4. SF was applied via a fluid stream generated through a pressurized perfusion system. No effect was observed at pH 7.4. Increased transient currents for each homomeric channel were observed when elevated SF was applied in conjunction with acidic pH (6.0–4.0). The sustained current was not (hASIC2a) or only slightly increased (hASIC1V3 and hASIC3a). SF-induced effects were not seen in water injected oocytes and were blocked by amiloride. Non-proton ligands activated a persistent current in hASIC1V3 and cASIC1 (MitTx) and hASIC3a (GMQ) at pH 7.4. Here SF caused a further current increase. Results suggest that ASICs do have an intrinsic ability to respond to mechanical force, supporting their role as mechanosensors in certain local environments.
Highlights
Acid-sensing ion channels (ASICs), formed by ASIC proteins, are members of the degenerin/epithelial Na+ channel protein superfamily[1]
Shear force at pH 7.4 has no effect on hASIC1V3, hASIC2a and hASIC3a activity
Oocytes expressing either hASIC1V3, hASIC2a or hASIC3a were placed into the recording chamber (Fig. 1) and exposed to shear force (SF) at pH 7.4
Summary
Acid-sensing ion channels (ASICs), formed by ASIC proteins, are members of the degenerin/epithelial Na+ channel protein superfamily[1] Members of this protein family were initially identified to form mechanoreceptors in Caenorhabditis elegans[2] and it is considered that their mechanosensitive function relies on an interaction with the extracellular matrix[3]. There is emerging evidence that in addition to protons, non-proton ligands can activate ASICs at physiological pH10 and a recent study reported that changes of local membrane lipid environments can activate ASIC3, independent of changes of pH11. This is important since it indicates that protons may not be the sole trigger for activating ASICs. As non-proton ligands a peptide complex from the www.nature.com/scientificreports/. Venom of the Texas coral snake (Micrurus tener tener, MitTx) was shown to activate ASIC1 at normal pH12 and 2-guanidine-4-methylquinazoline (GMQ), a small molecule that is similar to endogenously produced inflammatory mediators, was identified to activate ASIC3 at pH 7.413 and modulates pH responses of ASIC1 and 214
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