Ken Lee
BS, Microbiology, University of Toronto, Ontario
PhD, Molecular Genetics, University of Toronto, Ontario
My research centers on the ATP-sensitive potassium channel (KATP), which are found in the heart, vasculature and panaceas. KATP channels adjust cellular electrical activity according to availability of metabolic energy, in the form of ATP, to modulate physiological processes such as cardiac activity, blood pressure homeostasis and insulin secretion.
KATP channels are large hetero-octameric membrane protein complexes comprised of four Kir6 pore-forming subunits and four sulphonylurea receptor (SUR) regulatory subunits. Kir6 is an inward rectifier potassium channel, while SUR is an ABC transporter. ATP binds to Kir6 subunits, which favors pore closure; in contrast, MgADP binding to SUR subunits biases the pore toward opening, thus opposing ATP-inhibition.
A number of human channlopathies arise from KATP mutations that result in loss-of-function (e.g. hyperinsulinism) or gain-of-function (e.g. diabetes). These channelopathies establish KATP channels as drug targets. Clinically relevant KATP targeting compounds include Glimepiride (a sulphonlylurea derivative) and Diazoxide (a K-Channel Opener (KCO)), which are used for the management of type 2 diabetes and hypertension, respectively. Sulphonylureas and KCOs are thought to engage SUR subunits to effect KATP pore closure or opening, respectively.
The union of two distinct classes of membrane transport proteins as found in the KATP channel is unusual and begs the question: how does one create an ATP-sensitive ion channel by combining potassium channel and ABC transporter proteins? High-resolution structures of KATP should shed new light on its mechanism, but despite more than two decades since its discovery, a crystal structure of KATP is still at large. Thus, our understanding of how nucleotide and drug binding translate to the gating of KATP channels remains incomplete.
In the MacKinnon Lab, I apply structural and functional approaches to gain insight into how KATP channels couple cell metabolism to electrical output.
