Pharmacological rescue of trafficking-impaired KATP channels

Oregon Health & Science University, Portland OR

Investigators

Linked publications & trials

Abstract

? DESCRIPTION (provided by applicant): 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.