Study of ligand and mechanically gated ion channels

Abstract

Ion channels are a kind of essential proteins in many biological processes. In hearing and sense of pain, the 2 major senses of humans, ion channels are involved in maintaining the proper function of the two senses. In hearing, It is hypothesized that TMC1 is a protein that is the pore forming subunit of the mechanotransduction (MT) complex. Yet, due to the failure in expressing TMC1 on the cell surface of heterologous cell lines, the process of charaterizing TMC1 as an ion channel is hindered. Here, instead of using heterologous cell lines, we demonstrate that giant unilammar vesicles(GUV) could be a potential platform for characterizing ion-channels by using ionmycin and MscL channel as positive controls. In pain sensation, TRPV1 is a channel that proves to be involved in chronic neuropathic pain. Since the existing pain killer or antagonist of TRPV1 could not relieve patients with chronic neuropathic pain effectively without side-effects, new drugs targeting TRPV1 have to be found and evaluated. Here, we have demonstrated a drug screen on compounds orginated from marine bacteria. With complementary approaches including high-throughput dye-uptake drug screen, patch clamp electrophysiology, molecular docking and animal experiments, there is a reasonably high confidence that the two compounds F11 and F28 that we identified in our study are the inhibitors of TRPV1 and could potentially be developed into a commercial drug. Collectively, this project provides an insight into channel characterization and establishment of drug screening workflow for drugs that targets ion channels.

Date of Award	2021
Original language	English
Awarding Institution	The Hong Kong University of Science and Technology
Supervisor	Pingbo HUANG (Supervisor)