Kir6.1 and SUR2B in Cantú syndrome

Abstract

Kir6.1 and SUR2 are subunits of ATP-sensitive potassium (K_ATP) channels expressed in a wide range of tissues. Extensive study has implicated roles of these channel subunits in diverse physiological functions. Together they generate the predominant K_ATP conductance in vascular smooth muscle and are the target of vasodilatory drugs. Roles for Kir6.1/SUR2 dysfunction in disease have been suggested based on studies of animal models and human genetic discoveries. In recent years, it has become clear that gain-of-function (GoF) mutations in both genes result in Cantú syndrome (CS)-a complex, multisystem disorder. There is currently no targeted therapy for CS, but studies of mouse models of the disease reveal that pharmacological reversibility of cardiovascular and gastrointestinal pathologies can be achieved by administration of the K_ATP channel inhibitor, glibenclamide. Here we review the function, structure, and physiological and pathological roles of Kir6.1/SUR2B channels, with a focus on CS. Recent studies have led to much improved understanding of the underlying pathologies and the potential for treatment, but important questions remain: Can the study of genetically defined CS reveal new insights into Kir6.1/SUR2 function? Do these reveal new pathophysiological mechanisms that may be important in more common diseases? And is our pharmacological armory adequately stocked?

Keywords: ABCC9; Cantú syndrome; KCNJ8; channelopathy; smooth muscle.

Graphical abstract

Figure 1.

Kir6.1/SUR2 channel genes and structure. A: K_ATP channel encoding genes, ABCC8 and KCNJ11 encoding Kir6.2 and SUR1 are located on human chromosome 11p15.1; ABCC9 and KCNJ8 are located on chromosome 12p12.q. ABCC9 transcripts are subject to differential splicing to SUR2A and SUR2B by alternative inclusion of terminal 42 amino acid exons. B: cartoon structures of Kir6.1, a membrane of the 2-transmembrane domain family of inwardly rectifying potassium (Kir) channels, and SUR2 a member of the ABC-transporter family.

Figure 2.

Tissue mRNA expression of KCNJ8. Adapted from the ARCHS4 web resource (https://maayanlab.cloud/archs4/gene/KCNJ8) (26) with permission.

Figure 3.

Tissue mRNA expression of ABCC9. Adapted from the ARCHS4 web resource (https://maayanlab.cloud/archs4/gene/ABCC9) (26) with permission.

Figure 4.

Regulatory pathways for Kir6.1/SUR2B VSM K_ATP channels. K_ATP channels in VSM are activated by a range of mechanisms, including endothelial cell (EC)-derived nitric oxide (NO), and eicosanoids (EETs); Gαs-coupled receptors for adenosine, vasoactive intestinal peptide (VIP), GLP-1, and calcitonin gene-related peptide (CGRP), which increase channel activity via protein kinase A (PKA)-mediated phosphorylation of SUR2 and Kir6.1; lipid modulation including PIP2 and palmitoylation of Cys176; and metabolic regulation including increased intracellular ADP/ATP ratios, hypoxia, and acidification. Channels are inhibited by Gaq-coupled receptors for norepinephrine (NE), endothelin-1 (ET-1), angiotensin II (Ang II), vasopressin (AVP), serotonin (5-HT), histamine, and neuropeptide Y (NPY) via PKC phosphorylation of Kir6.1; increased intracellular ATP concentrations; and reactive oxygen species and superoxide involving glutathionylation (GSH) of Cys176 (, –53). VSM, vascular smooth muscle.

Figure 5.

Kir6.1/SUR2B structural features. A: top, cartoon of Kir6.1/SUR2B proteins color coded according to cryo-EM model (bottom). The “propeller” structure (pdb: 7MIT) (124) shows the Kir6.1 ATP binding sire (ATP shown as spheres), the Kir6.1 N-terminus (yellow), Kir6.1 C-terminus region implicated in PNU-37883 inhibition (shown as blue sticks), glibenclamide binding site (solid teal oval), and residues in TMD2 implicated in KCO binding (dashed blue circle) (125, 126). CS mutation sites in Kir6.1 (labeled) and throughout SUR2 shown as spheres. The Kir6.1 tetramer is shown alongside a SUR2B monomer (3 SUR2B subunits omitted for simplicity). B: top, primary amino-acid sequence of the extracellular “turret” region of Kir6.1 and Kir6.2. Bottom, unique turret region of Kir6.1 highlighted in orange. C: close-up view of glibenclamide binding site showing close apposition of Tyr1209 (pdb: 7MJO; human numbering; equivalent of Y1205 in rat clone) (124).

Figure 6.

CS-associated pathologies. A: multisystem pathologies observed in CS (images adapted from https://bioicons.com). Working models for cardiovascular (B) and GI (C) abnormalities in CS arising from GoF of vascular (B) or GI (C) smooth muscle K_ATP channels, and reversal by sulfonylureas (138, 139). CS, Cantú syndrome; GI, gastrointestinal tract; GoF, gain-of-function.