Show-Ling Shyng
Oregon Health & Science University, OR·Biophysics
Cells need a way to match their electrical activity to how much energy they have. ATP-sensitive potassium (KATP) channels do this.
- Fields
Biophysics
Pharmacology
Biochemistry
- Topics
KATP channels
ATP-sensitive potassium channels
Kir6.2
- Grants
- 3 known grants, through Mar 2031
What they work on
- Solve cryo-EM structures of pancreatic, cardiac and vascular KATP channels in closed and open states, to build a complete set showing how the channels open in response to ATP and ADP.
- Test how membrane lipids and flexible, intrinsically disordered protein regions control KATP channel activity, combining structural observations with electrophysiology recordings of channel currents.
- Compare KATP channel isoforms in drug-free, inhibitor-bound and activator-bound states, using cryo-EM, molecular dynamics simulations and functional assays, to explain each isoform's distinct nucleotide sensitivity and drug responses.
- Discover inhibitors of the vascular Kir6.1/SUR2B channel for Cantú syndrome, whose mutations make the channel overactive, using structure-based in silico compound screening followed by functional testing.
- Test whether pharmacological correctors restore surface expression, function and normal insulin secretion of trafficking-defective KATP mutants, using new human beta-cell lines and mouse models of congenital hyperinsulinism.
- Screen SUR1 nonsense mutations for rescue by Anti-Codon Engineered tRNAs, which let cells read past premature stop codons, then test insulin secretion correction in human beta-cell lines carrying these mutations.
More about the research
They are pores in the cell membrane that sense the energy molecules ATP and ADP inside the cell. In the pancreas, for example, they help link blood sugar to insulin release. Mutations in KATP channel genes cause serious diseases of the hormone system, heart, blood vessels, muscles and nerves, including congenital hyperinsulinism, neonatal diabetes, DEND syndrome and Cantú syndrome. The lab's long-term goal is to understand how these channels' structure determines their function, and to use that knowledge to design drugs that target one channel type without affecting others.
Why it matters
Faulty KATP channels cause severe diseases such as congenital hyperinsulinism, neonatal diabetes and Cantú syndrome. Patients with some forms of congenital hyperinsulinism have no effective drug and may need their pancreas removed, which leaves them with lifelong diabetes. Detailed channel structures could guide drugs that target one channel type, such as new vascular channel inhibitors for Cantú patients. Corrector drugs and ACE-tRNAs could offer new treatment approaches for children with hyperinsulinism.
Known grants
From NIH and NSF research grants. Labs often have other funding we can't see.
Closest labs
Conor McClenaghan
Rutgers University-New Brunswick, NJ·Pharmacology
Develop engineered split-SUR2 subunits, protein pieces of the KATP channel's regulatory partner, that can reassemble and restore ATP-sensitive potassium channel function in vivo, using protein engineering and patch clamp recordings.
Edward Twomey
Johns Hopkins University, MD·Biophysics
Determine how AMPA receptors, glutamate-activated channels that carry fast signals between neurons, open and close on a millisecond timescale, using time-resolved cryo-electron microscopy that captures rapid structural snapshots.
Danny Chou
Stanford University, CA·Chemistry
Define the molecular mechanism of insulin receptor antagonism and partial agonism, starting from an antagonistic insulin derivative the team discovered, and gather structural insights into how such molecules engage the receptor.
The school
Oregon Health & Science University: 24 labs on PI Pages, $545M a year on research, 54 research doctorates a year.
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