Synthetic Ion Channel Formed by Multiblock Amphiphile with Anisotropic Dual-Stimuli-Responsiveness

Abstract

Transmembrane proteins within biological membranes exhibit varieties of important functions that are vital for many cellular activities, and the development of their synthetic mimetics allows for deep understanding in related biological events. Inspired by the structures and functions of natural ion channels that can respond to multiple stimuli in an anisotropic manner, we developed multiblock amphiphile V F in this study. When V F was incorporated into the lipid bilayer membranes, V F formed a supramolecular ion channel whose ion transport property was controllable by the polarity and amplitude of the applied voltage. Microscopic emission spectroscopy revealed that V F changed its molecular conformation in response to the applied voltage. Furthermore, the ion transport property of V F could be reversibly switched by the addition of (R)-propranolol, an aromatic amine known as an antiarrhythmic agent, followed by the addition of β-cyclodextrin for its removal. The highly regulated orientation of V F allowed for an anisotropic dual-stimuli-responsiveness for the first time as a synthetic ion channel.

Supramolecular chemistry in lipid bilayer membranes

“…The research group of Kinbara have developed a variety of single molecule ion channels that respond to external stimuli such as ligands, 100 electric fields 101 or mechanical stress. 102 An impressive example includes a multi-block amphiphile (Figure 11B), which inserts itself into the bilayer in a controlled orientation due to its amphiphilic nature; allowing gating of ion transport activity with both agonistic and antagonistic ligands.…”

Supramolecular Transmembrane Ion Channels Formed by Multiblock Amphiphiles

“…2021, 143, 1348−1355. 4 A dimeric multiblock amphiphile possessing ligand-responsive phosphate units and voltage-responsive fluorinated aromatic units exhibits anisotropic and dual-stimuli-responsive transmembrane ion transport properties.…”

“…49−51 In this sense, MAs may provide great advantages for the realization of such a two-gate system owing to their ability to be incorporated within the membranes in a controlled molecular orientation and to respond to multiple external stimuli in an anisotropic manner across the membranes. 3,4 Another intriguing direction in this field is the modulation of biological phenomena by MAs. The MAs developed in our laboratory might open a new avenue to designing novel therapies for channelopathies by taking over the functions of disordered ion channel proteins.…”

“…Such responsiveness to multiple stimuli is highly advantageous because it enables the integration of multiple types of signals to realize functional control with high precision. We thus designed multiblock amphiphile MA-6 , which incorporated phosphate ester groups as ligand-binding units and fluorinated hydrophobic moieties possessing permanent dipole moments along their long axes as voltage-responsive units (Figure a) . Aromatic fluorination also contributes to the effective incorporation of MAs into the membranes, owing to the enhanced lipophilicity. , Interestingly, when MA-6 was incorporated into the membranes, it adopted a controlled transmembrane geometry with its phosphate ester groups located on the cis side of a BLM.…”

Properties of Imidazolinium-containing Multiblock Amphiphile in Lipid Bilayer Membranes

“…Meanwhile, the domain formation due to the lateral phase separation in lipid bilayer membrane has also been drawing interest, in association with raft formation which is considered to play important roles for controlling activity of membrane proteins [12][13][14]. We have been involved in development of multiblock amphiphiles which form stimuli-responsive ion channels [15][16][17][18][19][20][21] and thermally responsive assemblies in lipid bilayer membranes [22,23].…”