Graduate Studies Faculty

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Show-Ling Shyng, Ph.D.

Professor, Biochemistry and Molecular Biology, School of Medicine
Adjunct Professor, Physiology and Pharmacology, School of Medicine, OHSU
Admin Unit: SOM-Biochemistry & Molecular Biology Department
Phone: 503-494-2694
Lab Phone: 503-494-3682
Fax: 503-494-8393
Office: MRB 624
Mail Code: L224
Biochemistry & Molecular Biology
Neuroscience Graduate Program
Physiology & Pharmacology
Program in Molecular & Cellular Biosciences
Research Interests:
ion channel structure-function; electrophysiology; molecular genetics; disease mechanism; diabetes; signal transduction; protein folding and trafficking; proteomics; drug discovery; translational research » Click here for more about Dr. Shyng's research » PubMed Listing
Preceptor Rotations
Dr. Shyng has not indicated availability for preceptor rotations at this time.
Faculty Mentorship
Dr. Shyng has not indicated availability as a mentor at this time.

Research Interests

Our lab is interested in the biology of ion channels. Ion channels are membrane proteins that serve a wide variety of critical functions. Specifically our research focuses on an ATP-sensitive potassium (K-ATP) channel formed by two distinct protein subunits: a sulfonylurea receptor SUR1 and an inwardly rectifying potassium channel Kir6.2. Uniquely, K-ATP channels are gated by intracellular nucleotides ATP and ADP; ATP inhibits channel activity whereas MgADP stimulates channel activity.  These gating properties enable them to couple cell metabolism with cell excitability, thereby regulating a variety of physiological processes such as insulin secretion, neurotransmitter release, and cytoprotection during cardiac and cerebral ischemia. Dysfunction of K-ATP channels due to genetic mutations cause congenital hyperinsulinism, diabetes, neurological dysfunction and delayed cardiomyopathy. Current research is focused on the following projects.

Gating mechanism: The ability of K-ATP channels to sense metabolic changes rests primarily on the sensitivity of the channel to intracellular ATP and ADP. ATP inhibits channel activity by binding to the Kir6.2 subunit, and ADP stimulates channel activity by interacting with the SUR1 subunit. While biochemical evidence suggests that ATP hydrolysis at SUR1 drives the opening of Kir6.2, the structural mechanism underlying this functional coupling remains poorly understood. In addition to intracellular nucleotides, K-ATP channels are gated by membrane phosphoinositides such as phosphatidylinositol-4,5-bisphosphate (PIP2). PIP2 interacts primarily with the Kir6.2 subunit to stimulate channel activity and decrease the apparent ATP sensitivity of the channel. Using site-directed mutagenesis combined with patch-clamp recordings and biochemical experiments, we have previously identified amino acids in SUR1 and Kir6.2 involved in channel gating by ATP, ADP, and PIP2. We are now focusing on the secondary, tertiary, and quaternary structural elements involved in gating, with special interests in the role of subunit-subunit interactions in these processes.

K-ATP channel biogenesis and trafficking regulation: Besides gating, the number of an ion channel expressed in the plasma membrane is a critical determinant of the extent to which the ion channel contributes to membrane properties. What are the intrinsic and external parameters that govern the number of channels on the cell surface? We are interested in identifying both structural determinants within the channel proteins as well as the molecular chaperones present in the ER lumen and the cytosol that are important for the correct folding and assembly of K-ATP channel subunits. Using a proteomics approach, we have identified many channel-interacting proteins that may be involved in monitoring the folding, assembly and degradation of K-ATP channel proteins. Projects are ongoing to test if knockdown or overexpression of these molecules affect channel biogenesis and surface expression. In addition, we are interested in determining whether the channels, after passing the ER checkpoint and traversing the Golgi, are sorted into specific secretory granules prior to being delivered to the plasma membrane, and if so, the molecular mechanisms that govern these sorting events. Finally, we are interested in determining how the lifetime of the channel in the plasma membrane is affected by external stimuli such as hormones, neurotransmitters, glucose, and pharmacological agents that target pancreatic b-cells. We are currently using a combination of molecular, biochemical, electrophysiological, and live cell imaging techniques to address these questions.

Translational research on KATP channelopathy:  Loss-of-function mutations in SUR1 or Kir6.2 cause hyperinsulinism, whereas gain-of-function mutations result in neonatal diabetes and increased risk for type II diabetes. We are studying the molecular defects in channel biogenesis and gating caused by disease mutations to understand genotype-phenotype relationships in patients. This knowledge is important for disease diagnosis and the development of mechanism-based therapy. Importantly, we have recently discovered several chemical compounds that can correct channel folding and trafficking defects (called 'chemical chaperones') caused by disease mutations. We are currently developing a transgenic mouse model and using human pancreatic islets to further test the effects of these chemical chaperones. The ultimate goal is to translate our basic science findings to disease treatment.


Show-Ling Shyng received her B.S. in Zoology in 1984 from the National Taiwan University and her Ph.D. in Neurobiology and Behavior in 1990 from Cornell University. After spending a year as a postdoctoral fellow at the California Institute of Technology, she moved to Washington University where she was a research associate, and then a research assistant professor in the Department of Cell Biology and Physiology. She joined the CROET at OHSU as an Assistant Scientist in 1999 and became a Senior Scientist in 2009. In 2010, she moved to the Department of Biochemistry and Molecular Biology in the School of Medicine.



Selected Publications