Show-Ling Shyng, Ph.D., is a professor of biochemistry and molecular biology in the OHSU School of Medicine.

June 5, 2015

What projects are you currently working on and are there opportunities for fellow faculty to participate?

Research in my lab revolves around understanding the biology of KATP channels in health and disease. KATP channels are potassium channels that have uniquely evolved to couple metabolism with membrane excitability to regulate physiological responses appropriate to the energetic state of a cell. In pancreatic β-cells, these channels are critical for regulating insulin secretion and are the targets of the commonly-prescribed sulfonylurea drugs for type 2 diabetes patients. Genetic variations in the KATP channel genes underlie rare insulin secretion or neurological diseases that can be difficult to treat and can also increase the risk of type 2 diabetes.

A major project we are currently working on is to use single-particle cryo-electron microscopy and chemical crosslinking mass spectrometry-based protein mapping to obtain a high-resolution structure of the channel complex. This is a collaborative effort with Drs. James Chen and Larry David in our department. We hope this effort will aid in the design of new drugs that can combat rare diseases caused by channel mutations and that may also benefit the larger type 2 diabetes patient population. A second major project is to understand the signaling mechanism by which leptin, the “satiety” hormone secreted by fat cells, regulates trafficking of KATP channels in pancreatic β-cells. We have recently shown that leptin recruits KATP channels to the cell membrane to inhibit glucose-stimulated insulin secretion. Our preliminary studies suggest that this regulatory mechanism is also employed by some hypothalamic neurons involved in energy homeostasis. By identifying the molecular players involved in this regulation, we may uncover novel drug targets for metabolic diseases such as diabetes and obesity.

What is the most important aspect of support that OHSU provides to you currently and how would you like this or other support to grow in the future?

The intellectual environment provided by my colleagues in the basic science and clinical departments in the OHSU School of Medicine as well as in the research institutes has been vital to our research program. The wide range of research expertise at OHSU makes it possible to explore new research projects. In addition, the opportunity to work with high quality, enthusiastic graduate students has been important in providing an exciting and rewarding research environment. I would like to see continued efforts to increase faculty and graduate program support.

A hypothetical: If you could have one tool that would solve a seemingly impenetrable problem in your work, what would it do? You have unlimited resources to design this tool, so think big.

Many KATP channel mutations cause severe diseases by preventing proper folding and assembly of channel proteins in the early secretory compartments. We have been testing small molecules that can overcome such defects. So far, our “low-throughput” studies have identified a few promising compounds, but unfortunately these compounds also block channel function. Identification of additional small molecules that correct channel folding defects without impairing channel function is greatly needed for patients with these devastating diseases. A university shared resource that has the capability for high-throughput drug screening, computer-aided drug design and chemical synthesis would greatly facilitate our drug discovery effort.

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