Personalized Therapeutics for KATP-Dependent Pathologies

Abstract

Ubiquitously expressed throughout the body, ATP-sensitive potassium (K_ATP) channels couple cellular metabolism to electrical activity in multiple tissues; their unique assembly as four Kir6 pore-forming subunits and four sulfonylurea receptor (SUR) subunits has resulted in a large armory of selective channel opener and inhibitor drugs. The spectrum of monogenic pathologies that result from gain- or loss-of-function mutations in these channels, and the potential for therapeutic correction of these pathologies, is now clear. However, while available drugs can be effective treatments for specific pathologies, cross-reactivity with the other Kir6 or SUR subfamily members can result in drug-induced versions of each pathology and may limit therapeutic usefulness. This review discusses the background to K_ATP channel physiology, pathology, and pharmacology and considers the potential for more specific or effective therapeutic agents.

Keywords: Cantú syndrome; Kir6.1; Kir6.2; SUR1; SUR2; congenital hyperinsulinism; neonatal diabetes.

Figure 1

Molecular regulation of ATP-sensitive potassium (K_ATP) channels (a) K_ATP channels are octameric complexes in which four pore-forming inward rectifier potassium channel (Kir6) subunits generate the channel pore and four sulfonylurea receptor (SUR) subunits serve the regulatory role. Each Kir6 subunit consists of two transmembrane helices (M1, M2) and a reentrant pore loop that forms the K selectivity filter. Each SUR subunit consists of three major domains, the unique 5 helix TM0 and the ATP-binding cassette (ABC) core 6 helix TM1 and TM2 domains, each of which are followed by linker between TM0 and TM1 (L0), nucleotide-binding fold 1 (NBF1), and NBF2, respectively. (b) The major physiological regulation is via a gate at the cytoplasmic end of the inner cavity. ATP binding to the Kir6 cytoplasmic region provides the energetic push to close channels. Magnesium-bound ATP (MgATP) binding at the ATP-binding site (ABS1) formed at the NBF1-NBF2 interface, together with ATP hydrolysis or magnesium-bound ADP (MgADP) binding at ABS2, results in a conformational activated state that is transduced to override ATP inhibition. Phosphatidyl inositol 4,5 bisphosphate (PIP₂) interaction at a site near the ATP inhibitory site also provides an energetic pull to open channels. Pharmacologically, sulfonylureas (SUs) or K channel openers (KCOs), interacting with sites at the TM1/2 interface, respectively, promote channel closure or opening. (c) Model of the Kir6.2/SUR1 channel constructed from a cryo-electron microscopy density map, viewed from the side (left) and from the extracellular side (right). Key features are indicated, including transmembrane domains (TMDs), intracellular NBFs [referred to as nucleotide-binding domains (NBDs)], and the C-terminal domain (CTD). Panel c adapted with permission from Reference .

Figure 2

Sulfonylurea inhibition of K_ATP channels. (a) Kir6.2/sulfonylurea receptor subunit 1 (SUR1)-dependent K_ATP channel activity as a function of [tolbutamide], recorded in inside-out patches, shows biphasic inhibition. Dashed lines and blue circles show wild-type (WT) channel activity. Tolbutamide sensitivity is unaffected by transient neonatal diabetes mellitus (NDM) mutant Kir6.2[I182V] but is reduced by permanent NDM mutants V59M and Q52R and abolished by the developmental delay, epilepsy, and neonatal diabetes (DEND) syndrome mutation Kir6.2[I296L] (significance indicated: *P < 0.05 and **P < 0.01). Even in the heterozygous condition (mixed wild type and I296L), high-affinity tolbutamide sensitivity is markedly reduced. Panel a adapted from Reference . (b) A structural model of the repaglinide (RPG)-bound SUR1 ATP-binding cassette transporter core module viewed from the side shows the slice viewed from the top and side (indicated by the two gray lines) at higher magnification to the right. The pharmacochaperone pocket is shown from the top and the side of the channel in the states indicated. Ligand density corresponding to RPG is shown in magenta, carbamazepine (CBZ) in red, and glibenclamide (GBC) in blue. (c) The Kir6.2 N-terminal cryo-electron microscopy density (pink mesh) is superposed with the polyalanine model shown in the RPG-bound (green) SUR1 structural model. The piperidino moiety of RPG is highlighted to show close proximity to the N-terminal methionine of the modeled Kir6.2 N-terminal peptide. The close proximity of SUR1 residue C1142 and Kir6.2 residue L2 is also highlighted. Panels b and c adapted with permission from Reference .

Figure 3

KCO action and crossover drug-induced pathologies in K_ATP channels. (a, left) Cryo- electron microscopy density map shows SUR1 in complex with Mg nucleotides and NN414 (viewed from the side). TMD1-NBD1, TMD2-NBD2, and NN414 are colored in pink, blue, and red, respectively. (Right) Close-up views of the NN414-binding site. TMD1 and TMD2 are colored in pink and blue, respectively. NN414 (orange) and residues that interact with NN414 are shown as sticks. Panel a adapted with permission from Reference . (b) Canonical K_ATP channels are formed by the products of the ABCC8/KCNJ11 and ABCC9/KCNJ8 gene pairs. LOF mutations in either subunit of each pair (causing CHI and AIMS, respectively) and GOF mutations (causing NDM and Cantú syndrome, respectively) may be treatable with channel-activating KCOs or inhibitory SUs. However, crossover effects on the unaffected channels encoded by the other gene pair cause inevitable side effects. (c) Hypertrichosis and fluid retention characterize both Cantú syndrome, caused by a Kir6.1/SUR2 GOF mutation, and CHI when treated with diazoxide. Images in panel c reproduced with permission from References and . Abbreviations: AIMS, ABCC9-related intellectual disability myopathy syndrome; CHI, congenital hyperinsulinism; GI, gastrointestinal; GOF, gain-of-function; K_ATP, ATP-sensitive potassium; KCO, K_ATP channel opener; Kir, pore-forming inward rectifier potassium channel subunit; LOF, loss-of-function; NBD, nucleotide-binding domain; NDM, neonatal diabetes mellitus; SU, sulfonylurea; SUR, sulfonylurea receptor subunit; SVR, systemic vascular resistance; TM, transmembrane; TMD, transmembrane domain.