Kir6.1 and SUR2B in Cantú syndrome

Abstract

Kir6.1 and SUR2 are subunits of ATP-sensitive potassium (KATP) channels expressed in a wide range of tissues. Extensive study has implicated roles for these channel subunits in diverse physiological functions. Together they generate the predominant KATP 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 Cantu Syndrome (CS) - a complex, multi-system 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 KATP 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 to Kir6.1/SUR2 function? Do these reveal new pathophysiological mechanisms that may be important in more common disease? And is our pharmacological armoury adequately stocked.

Mechanistic insights on KATP channel regulation from cryo-EM structures

“…Together, K ATP channels govern a broad range of vital physiological processes, from hormone secretion, skeletal muscle and vascular smooth muscle contraction, cardiac action potential shortening during metabolic stress, to learning and memory. K ATP channel dysfunction underlies several human diseases, including congenital hyperinsulinism ( Galcheva et al, 2019 ; Rosenfeld et al, 2019 ), neonatal diabetes and DEND (developmental delay, epilepsy, and neonatal diabetes) syndrome ( Pipatpolkai et al, 2020 ), and Cantú syndrome ( McClenaghan and Nichols, 2022 ). In keeping with their importance in human physiology and pathophysiology, K ATP channels are drug targets for a variety of human conditions ( Foster and Coetzee, 2016 ; Kharade et al, 2016 ).…”

A Cantú syndrome mutation produces dual effects on KATP channels by disrupting ankyrin B regulation

“…Therefore, the effects here reported would be manifested preferentially in those cells expressing K ATP channels mostly composed of Kir6.2+SUR2A subunits as in atrial and ventricular myocytes although channels composed by Kir6.2+SUR2A subunits can be also found in other cell types ( Nichols et al, 2013 ). Recent evidence suggests that many of the CS manifestations due to ABCC9 mutations are preferentially due to altered K ATP channels containing Kir6.1 rather than Kir6.2 subunits ( McClenaghan and Nichols, 2022 ). However, there are several CS symptoms (e.g., at the cardiovascular or neurological level) that support the importance of the mutation consequences on Kir6.2-containing channels.…”

“…Furthermore, the demonstration that SUR2A and AnkB may interact and that the p.S1054Y mutation reduces the intensity of the interaction also indicates that the consequences of the mutation will be apparent irrespective of the Kir6.x pore-forming subunit. Growing evidence suggests that CS manifestations predominate in tissues where SUR2B subunits are more expressed than SUR2A ( Davis et al, 2020 ; McClenaghan and Nichols, 2022 ). SUR2A and SUR2B are two splice variants encoded by the ABCC9 gene that vary only in the last 42 amino acids ( Hibino et al, 2010 ).…”

“…Cantú syndrome (CS; ORPHA: 1517) is a genetically determined rare disease characterized by hypertrichosis, craniofacial dysmorphology, and neurological, intellectual, and cardiovascular alterations including cardiomegaly, systemic hypotension, persistent ductus arteriosus, alterations in the electrocardiogram, and pulmonary hypertension ( Nichols et al, 2013 ; Huang et al, 2018 ). CS is caused by mutations in ABCC9 and less frequently in KCNJ8 , which lead to K ATP channel hyperactivity due to a reduced block of the channel by physiological ATP concentrations ( Nichols et al, 2013 ; Grange et al, 2019 ; Harakalova et al, 2012 ; Brownstein et al, 2013 ; McClenaghan and Nichols, 2022 ). The mutations can increase the activating effects of Mg nucleotides that would eventually override ATP block or modify the ATP-binding site within Kir6.x subunit, thus reducing channel sensitivity for ATP ( Nichols et al, 2013 ; Grange et al, 2019 ; Harakalova et al, 2012 ; Cooper et al, 2015 ; McClenaghan et al, 2018 ).…”

Zoledronic Acid Blocks Overactive Kir6.1/SUR2-Dependent KATP Channels in Skeletal Muscle and Osteoblasts in a Murine Model of Cantú Syndrome

“…Cantú Syndrome (CS) is a rare autosomal-dominant, a multi-organ condition characterized by cardiomegaly, vascular dilation, low blood pressure, hypertrichosis, neuromuscular symptoms, and skeletal malformations [ 1 , 2 , 3 ]. CS is caused by gain-of-function (GOF) mutations in the ABCC9 and KCNJ8 genes [ 4 , 5 ], encoding the SUR2 and Kir6.1 subunits, respectively, of ATP-sensitive potassium (KATP) channels.…”