Lessons from KATP Channels with Diabetogenic Mutations in Sulfonylurea Receptor 1 (SUR1)

Abstract

Numerous mutations have been identified in SUR1 (ABCC8) subunit of the neuroendocrine type KATP channel in subjects with neonatal diabetes, neonatal diabetes plus epilepsy and/or other neurological features, maturity-onset diabetes of young, and later-onset diabetes. Patch-clamping, single-channel kinetics analysis, affinity photolabeling and molecular modeling were used to clarify how diabetogenic mutations in different parts of SUR1 affect open probability and sulfonylurea inhibition of SUR1/Kir6.2 KATP channel. Essentially all tested diabetogenic mutations in the canonical TMD1-NBD1-TMD2-NBD2 ABC exporter core of SUR1 hyperactivated KATP by stabilizing the stimulatory Mg-nucleotide bound (outward facing) state of SUR1 without affecting the intrinsic gating of KATP channel or its sensitivity to inhibitory nucleotides. Hyperstimulated mutant channels showed attenuated sulfonylurea inhibition in the presence, but not the absence, of stimulatory MgATP/ADP, indicating that KATP with SUR1 in the inward facing state has the lowest Kd for sulfonylureas. Diabetogenic mutations in the non-canonical TMD0-L0 part of SUR1 hyperactivated KATP by destabilizing its long-lived closed state with the highest affinity to inhibitory ATP or by strengthening the functional coupling between the MgATP/ADP-bound SUR1 core and the active (burst) state of the Kir pore. Mutations destabilizing the long-lived closed state compromised sulfonylurea inhibition of KATP in the absence of nucleotides but not the drug-induced release of stimulatory nucleotides. The findings support the mechanistic model (FEBS Letters, 585:3555-9) in which the TMD0-L0 module couples the SUR1 core with the KATP pore, define the most common ABCC8-associated mechanisms of KATP hyperactivity, and largely explain why the majority of diabetic subjects with mutant SUR1 require body-weight normalized doses of sulfonylureas exceeding those recommended by the FDA for treatment of common type 2 diabetes.