Yu-Wen Lin

Address:
Department of Cell Biology and Physiology
Washington University School of Medicine
Box 8228
660 South Euclid Avenue
St. Louis, MO 63110, U.S.A.

Telephone: 314-362-6629
FAX No.: 314-362-7463
E-mail: ywlin@wustl.edu

Research

ATP sensitive Potassium (KATP) channels are widely expressed in Pancreas, Heart, smooth muscles and brain therefore play important roles in regulating insulin secretion, performing cytoprotection in cardiomyocytes, regulating muscle tone and neuronal activity. Pancreatic KATP channels control insulin secretion by linking glucose metabolism to membrane excitability. These channels are octamers consisting of two distinct subunits, four inwardly rectifying potassium channel (Kir6.1 or Kir6.2) subunits and four sulfonylurea receptor (SUR1 or SUR2) subunits. In beta cells, Kir6.2 forms the channel pore and SUR1 play an important role in regulating both trafficking and gating of the pore complex. Kir6.2 is responsible for the gating action of ATP, which closes the channel. On the other hand, membrane phospholipids such as PIP2 and fatty acids metabolites such as long chain acyl CoA activate the channel through this Kir6.2 subunit. SUR1 belongs to the ATP binding cassette superfamily and has two nucleotide-binding domains (NBD) in the intracellular site. Physiologically MgADP interacts with SUR1 to activate the channel by binding to the NBD. Sulfonylurea drugs such as glibenclamide and tolbutamide bind to the SUR subunit and inhibit the KATP channel activity and are widely used to treat Type 2 Diabetes patients to stimulate their insulin secretion.

So far several homologous inwardly rectifying potassium channel structures (Kir3.1/Kir2.1/KirBac1.1) have been crystallized. However, the detailed gating motions and molecular mechanisms of how the Kir6 subunit is gated by various cellular regulators and how SUR regulate Kir6 subunit physiologically and pharmacologically are still being worked out. Moreover, how the SUR subunit is functionally coupled to Kir subunit in an octamer to form the functional channel and the interactions between SUR nucleotide-binding domains are still unclear. My goal is to gain insight to the gating of the channel and move toward more understanding of the structure-functional relationship in KATP channels.