Genetic mutations in the pancreatic beta cell ATP-sensitive K (KATP) channel underlie congenital + hyperinsulinism (CHI), a disorder characterized by persistent insulin release despite severe hypoglycemia. Normally, the KATP channel acts as a gatekeeper for insulin secretion by coupling intracellular glucose metabolism to the beta cell membrane potential. In CHI, loss-of-function mutations result in either defective gating, such that channels are always closed, or defective trafficking, such that channels never reach the cell surface. The central objective of this proposal is to understand why mutations within certain regions of the KATP channel lead to defective trafficking. We have recently identified compounds that can correct these trafficking defects called pharmacological chaperones (PCs), and a second objective of this proposal is to understand the detailed mechanism of PC action on these mutant channels. Preliminary evidence shows that many of these trafficking-impaired channels are functional once rescued to the cell surface. Thus a third objective is to demonstrate that trafficking mutations do not impart any functional defect and then to establish the feasibility of using PCs as a potential treatment for CHI. This work is significant because i) we have little understanding of how trafficking mutations actually disrupt channel biogenesis to cause CHI; ii) very little is known about how PCs overcome trafficking defects; iii) there are very limited treatment options available for this disease. This work is bot basic and applied in that it attempts to understand how heteromeric ion channels assemble and are regulated physiologically and pharmacologically, but does so within the context of a relevant and challenging disease.

Public Health Relevance

Protein misfolding and misassemble underlie many diverse disease states. These include Alzheimer's and Parkinson's disease, which are due to aggregation and accumulation of misfolded proteins, but also include cystic fibrosis, lysosomal storage disease, and congenital hyperinsulinism (CHI), which are all loss-of-function disorders due to degradation and clearance of misfolded proteins. CHI in particular is often caused by folding defects in the KATP channel, causing excess insulin secretion. Pharmacological chaperones may offer an alternative treatment to many of these diseases by correcting or preventing protein folding defects. The proposed research investigates the interactions between pharmacological chaperones and the KATP channel in order to provide a rationale for the use of these drugs as an alternative therapy for CHI.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31DK105800-02
Application #
9087004
Study Section
Special Emphasis Panel (ZDK1)
Program Officer
Castle, Arthur
Project Start
2015-05-13
Project End
2018-05-12
Budget Start
2016-05-13
Budget End
2017-05-12
Support Year
2
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Oregon Health and Science University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
Martin, Gregory M; Kandasamy, Balamurugan; DiMaio, Frank et al. (2017) Anti-diabetic drug binding site in a mammalian KATP channel revealed by Cryo-EM. Elife 6:
Martin, Gregory M; Yoshioka, Craig; Rex, Emily A et al. (2017) Cryo-EM structure of the ATP-sensitive potassium channel illuminates mechanisms of assembly and gating. Elife 6:
Martin, Gregory M; Rex, Emily A; Devaraneni, Prasanna et al. (2016) Pharmacological Correction of Trafficking Defects in ATP-sensitive Potassium Channels Caused by Sulfonylurea Receptor 1 Mutations. J Biol Chem 291:21971-21983