Advertisement

Commentary Free access | 10.1172/JCI135759

The surprising complexity of KATP channel biology and of genetic diseases

Guiling Zhao,1 Aaron Kaplan,1,2 Maura Greiser,1 and W. Jonathan Lederer1

1Center for Biomedical Engineering and Technology and Department of Physiology,

2Department of Medicine and Division of Cardiology, University of Maryland Baltimore, School of Medicine, Baltimore, Maryland, USA.

Address correspondence to: W. Jonathan Lederer, University of Maryland Baltimore, School of Medicine, 111 S. Penn Street, Baltimore, Maryland 21201, USA. Phone: 410.706.4895; Email: jlederer@som.umaryland.edu.

Find articles by Zhao, G. in: JCI | PubMed | Google Scholar

1Center for Biomedical Engineering and Technology and Department of Physiology,

2Department of Medicine and Division of Cardiology, University of Maryland Baltimore, School of Medicine, Baltimore, Maryland, USA.

Address correspondence to: W. Jonathan Lederer, University of Maryland Baltimore, School of Medicine, 111 S. Penn Street, Baltimore, Maryland 21201, USA. Phone: 410.706.4895; Email: jlederer@som.umaryland.edu.

Find articles by Kaplan, A. in: JCI | PubMed | Google Scholar |

1Center for Biomedical Engineering and Technology and Department of Physiology,

2Department of Medicine and Division of Cardiology, University of Maryland Baltimore, School of Medicine, Baltimore, Maryland, USA.

Address correspondence to: W. Jonathan Lederer, University of Maryland Baltimore, School of Medicine, 111 S. Penn Street, Baltimore, Maryland 21201, USA. Phone: 410.706.4895; Email: jlederer@som.umaryland.edu.

Find articles by Greiser, M. in: JCI | PubMed | Google Scholar

1Center for Biomedical Engineering and Technology and Department of Physiology,

2Department of Medicine and Division of Cardiology, University of Maryland Baltimore, School of Medicine, Baltimore, Maryland, USA.

Address correspondence to: W. Jonathan Lederer, University of Maryland Baltimore, School of Medicine, 111 S. Penn Street, Baltimore, Maryland 21201, USA. Phone: 410.706.4895; Email: jlederer@som.umaryland.edu.

Find articles by Lederer, W. in: JCI | PubMed | Google Scholar |

Published February 17, 2020 - More info

Published in Volume 130, Issue 3 on March 2, 2020
J Clin Invest. 2020;130(3):1112–1115. https://doi.org/10.1172/JCI135759.
© 2020 American Society for Clinical Investigation
Published February 17, 2020 - Version history
View PDF

Related article:

Glibenclamide reverses cardiovascular abnormalities of Cantu syndrome driven by KATP channel overactivity
Conor McClenaghan, … , Maria S. Remedi, Colin G. Nichols
Conor McClenaghan, … , Maria S. Remedi, Colin G. Nichols
Concise Communication Cardiology Vascular biology

Glibenclamide reverses cardiovascular abnormalities of Cantu syndrome driven by KATP channel overactivity

Abstract

Cantu syndrome (CS) is a complex disorder caused by gain-of-function (GoF) mutations in ABCC9 and KCNJ8, which encode the SUR2 and Kir6.1 subunits, respectively, of vascular smooth muscle (VSM) KATP channels. CS includes dilated vasculature, marked cardiac hypertrophy, and other cardiovascular abnormalities. There is currently no targeted therapy, and it is unknown whether cardiovascular features can be reversed once manifest. Using combined transgenic and pharmacological approaches in a knockin mouse model of CS, we have shown that reversal of vascular and cardiac phenotypes can be achieved by genetic downregulation of KATP channel activity specifically in VSM, and by chronic administration of the clinically used KATP channel inhibitor, glibenclamide. These findings demonstrate that VSM KATP channel GoF underlies CS cardiac enlargement and that CS-associated abnormalities are reversible, and provide evidence of in vivo efficacy of glibenclamide as a therapeutic agent in CS.

Authors

Conor McClenaghan, Yan Huang, Zihan Yan, Theresa M. Harter, Carmen M. Halabi, Rod Chalk, Attila Kovacs, Gijs van Haaften, Maria S. Remedi, Colin G. Nichols

×
Abstract

The ATP-sensitive K+ channel (KATP) is formed by the association of four inwardly rectifying K+ channel (Kir6.x) pore subunits with four sulphonylurea receptor (SUR) regulatory subunits. Kir6.x or SUR mutations result in KATP channelopathies, which reflect the physiological roles of these channels, including but not limited to insulin secretion, cardiac protection, and blood flow regulation. In this issue of the JCI, McClenaghan et al. explored one of the channelopathies, namely Cantu syndrome (CS), which is a result of one kind of KATP channel mutation. Using a knockin mouse model, the authors demonstrated that gain-of-function KATP mutations in vascular smooth muscle resulted in cardiac remodeling. Moreover, they were able to reverse the cardiovascular phenotypes by administering the KATP channel blocker glibenclamide. These results exemplify how genetic mutations can have an impact on developmental trajectories, and provide a therapeutic approach to mitigate cardiac hypertrophy in cases of CS.

Structural heterogeneity of the KATP channels

The ATP-sensitive K+ channel (KATP) is composed of a large macromolecular complex in which four inwardly rectifying K+ channel (Kir6.1 or Kir6.2, referred to herein as Kir6.x) subunits form a central pore surrounded by four regulatory sulphonylurea receptor (SUR) subunits (SUR1, SUR2A, or SUR2B) (1). Kir6.x and SUR assemble freely to form a functional KATP channel (Table 1) (1). The structural heterogeneity of the KATP channel leads to a huge variation of its functionality between and within different tissues. The diverse functions subserved by the KATP channels have been of increasing interest and reflect established roles such as in insulin secretion (2, 3) and newly identified functions such as controlling blood flow in the heart (4). Channelopathies of KATP channels have now become a focus because some of the diseases or syndromes have been found to be directly related to or caused by the mutations in subunits of KATP channels. Cantu syndrome (CS), for example, is one such disease characterized by gain-of-function (GoF) pathogenic variants in ABCC9 (ATP Binding Cassette Subfamily C Member 9), and less commonly, in KCNJ8 (Potassium Inwardly Rectifying Channel Subfamily J Member 8) (5). These genes encode SUR2 and Kir6.1 subunits, respectively of KATP channels. In this issue of the JCI, Colin Nichols and his team reported on their discovery that glibenclamide, a KATP channel (SUR) blocker, can reverse cardiac hypertrophy to correct some of the cardiovascular dysfunctions in CS and alleviate the symptoms of CS (6).

Table 1

KATP subunit composition by system, organ, tissue, and cell type

The complexity of CS and other genetic diseases

McClenaghan et al. (6) used a CS mouse model in which ABCC9 or KCNJ8 mutations were expressed in the smooth muscle cells (SMCs). In this model, the KATP channels in SMCs become overactive to recapitulate CS in the heart and vasculature. The apparent simplicity of mutations in the KATP channel subunits and of many other genetic diseases belies the complexity of their presentations. CS shares a property with many other genetic diseases where the mechanisms underlying the tissue complexities are not obvious. In the case of CS, for example, soft tissue and bone changes occur and how they arise mechanistically from the KATP channel mutations is unclear. Table 1 shows a compendium of KATP channel subunit composition by organ system and tissue and cell type, and reports on the related phenotypes in CS (5). We are, for example, still uncertain exactly why there is increased hair growth. How are all of these aspects of CS mechanistically linked to the mutations of the KATP channel subunits? A broad understanding of the molecular origins of the specific manifestations of CS is absent. However, our observations in CS are similar to those found in many other genetic diseases with components that develop over time and that probably arise indirectly from primary mutations. Examples are wide-ranging and could include autism in Timothy’s syndrome, memory dysfunction in presenilin-1–linked Alzheimer’s disease, the origins of complex gait dysfunctions in Parkin-dependent Parkinson’s disease, or enhanced/excessive X-ROS signaling in Duchenne Muscular Dystrophy. These specific manifestations of known genetic diseases have much to do with the chain of biological changes that somehow depends on the primary mutation (including possible epigenetic consequences) of these diseases. While the changes are associated with the diseases, they also constitute a profound warning to us. It is important to acknowledge our incomplete understanding of genetic diseases and their complex consequences, which arise from a focused genetic anomaly. Such a situation may mean that simple genetic corrections could constitute incomplete therapies, particularly when instituted late in the arc of the disease expression. We still need to be exquisitely careful when we attempt to make apparently simple and direct genetic corrections. As we improve our knowledge, though, we also need to develop useful treatments for affected individuals with known genetic diseases even if the corrections are incomplete.

Clinical implications

Adoption of any new therapeutic option necessitates minimal side effects. Sulfonylureas inhibit both SUR1 and SUR2 subunits, and therefore inhibit beta cell KATP channels, resulting in increased insulin secretion. Clinically, the most common side effect of sulfonylurea use is hypoglycemia, which would be a feared complication of initiating this therapy in nondiabetic patients. In the current study by McClenaghan et al. (6), the authors treated a CS mouse model with glibenclamide (Glyburide), a well-known and widely used medication with established FDA approval. Glibenclamide was well tolerated, even at the high doses required to reverse the cardiomyopathy. Treated mice experienced transient hypoglycemia, which resolved by the second day of therapy.

It was recently reported that an infant with CS (ABCC9 variant) and severe pulmonary hypertension was initiated on glibenclamide after failing to improve on standard therapy; treatment was well tolerated by the patient with nominal hypoglycemic episodes that resolved spontaneously (7). While future therapies may directly target CS-specific subunits, these early results with glibenclamide use in CS provide hope for an existing FDA-approved, off-the-shelf therapy. In humans, this approach is practical and palliative (7) and should fill the gap in treatment approaches until a better understanding of CS enables a cure.

Acknowledgments

This work was supported by NIH 1R01HL142290, 1R01HL140934, and 1R01AR071618 (WJL), the Department of Medicine & Division of Cardiology (AK), and the Center for Biomedical Engineering and Technology, University of Maryland School of Medicine (GZ, MG).

Footnotes

Conflict of interest: The authors declare that no conflict of interest exists.

Copyright: © 2020, American Society for Clinical Investigation.

Reference information:J Clin Invest. 2020;130(3):1112–1115. https://doi.org/10.1172/JCI135759.

See the related article at Glibenclamide reverses cardiovascular abnormalities of Cantu syndrome driven by K.

References
  1. Foster MN, Coetzee WA. KATP channels in the cardiovascular system. Physiol Rev. 2016;96(1):177–252.
    View this article via: PubMed CrossRef Google Scholar
  2. Ashcroft FM, Harrison DE, Ashcroft SJ. Glucose induces closure of single potassium channels in isolated rat pancreatic beta-cells. Nature. 1984;312(5993):446–448.
    View this article via: PubMed CrossRef Google Scholar
  3. Inagaki N, et al. Reconstitution of IKATP: an inward rectifier subunit plus the sulfonylurea receptor. Science. 1995;270(5239):1166–1170.
    View this article via: PubMed CrossRef Google Scholar
  4. Zhao G, Joca HC, Nelson MT, Lederer WJ. ATP-dependent and voltage-regulated blood flow in heart: electro-metabolic signaling. Proc Natl Acad Sci U S A. In press.
  5. Grange DK, et al. Cantú syndrome: Findings from 74 patients in the International Cantú Syndrome Registry. Am J Med Genet C Semin Med Genet. 2019;181(4):658–681.
    View this article via: PubMed CrossRef Google Scholar
  6. McClenaghan C, et al. Glibenclamide reverses cardiovascular abnormalities of Cantu syndrome driven by KATP channel overactivity. J Clin Invest. 2020;130(3):1116–1121.
    View this article via: JCI CrossRef Google Scholar
  7. Ma A, et al. Glibenclamide treatment in a Cantú syndrome patient with a pathogenic ABCC9 gain-of-function variant: Initial experience. Am J Med Genet A. 2019;179(8):1585–1590.
    View this article via: PubMed Google Scholar
  8. Sakura H, Ammälä C, Smith PA, Gribble FM, Ashcroft FM. Cloning and functional expression of the cDNA encoding a novel ATP-sensitive potassium channel subunit expressed in pancreatic beta-cells, brain, heart and skeletal muscle. FEBS Lett. 1995;377(3):338–344.
    View this article via: PubMed CrossRef Google Scholar
  9. Flagg TP, et al. Differential structure of atrial and ventricular KATP: atrial KATP channels require SUR1. Circ Res. 2008;103(12):1458–1465.
    View this article via: PubMed CrossRef Google Scholar
  10. Mederos y Schnitzler M, Derst C, Daut J, Preisig-Müller R. ATP-sensitive potassium channels in capillaries isolated from guinea-pig heart. J Physiol (Lond). 2000;525(Pt 2):307–317.
    View this article via: PubMed Google Scholar
  11. Isomoto S, et al. A novel sulfonylurea receptor forms with BIR (Kir6.2) a smooth muscle type ATP-sensitive K+ channel. J Biol Chem. 1996;271(40):24321–24324.
    View this article via: PubMed CrossRef Google Scholar
  12. Aziz Q, et al. ATP-sensitive potassium channels in the sinoatrial node contribute to heart rate control and adaptation to hypoxia. J Biol Chem. 2018;293(23):8912–8921.
    View this article via: PubMed CrossRef Google Scholar
  13. Li L, Wu J, Jiang C. Differential expression of Kir6.1 and SUR2B mRNAs in the vasculature of various tissues in rats. J Membr Biol. 2003;196(1):61–69.
    View this article via: PubMed CrossRef Google Scholar
  14. Aziz Q, Li Y, Anderson N, Ojake L, Tsisanova E, Tinker A. Molecular and functional characterization of the endothelial ATP-sensitive potassium channel. J Biol Chem. 2017;292(43):17587–17597.
    View this article via: PubMed CrossRef Google Scholar
  15. Yoshida H, Feig JE, Morrissey A, Ghiu IA, Artman M, Coetzee WA. K ATP channels of primary human coronary artery endothelial cells consist of a heteromultimeric complex of Kir6.1, Kir6.2, and SUR2B subunits. J Mol Cell Cardiol. 2004;37(4):857–869.
    View this article via: PubMed CrossRef Google Scholar
  16. Bondjers C, et al. Microarray analysis of blood microvessels from PDGF-B and PDGF-Rbeta mutant mice identifies novel markers for brain pericytes. FASEB J. 2006;20(10):1703–1705.
    View this article via: PubMed CrossRef Google Scholar
  17. Cao C, Lee-Kwon W, Silldorff EP, Pallone TL. KATP channel conductance of descending vasa recta pericytes. Am J Physiol Renal Physiol. 2005;289(6):F1235–F1245.
    View this article via: PubMed CrossRef Google Scholar
  18. Zawar C, Plant TD, Schirra C, Konnerth A, Neumcke B. Cell-type specific expression of ATP-sensitive potassium channels in the rat hippocampus. J Physiol (Lond). 1999;514(Pt 2):327–341.
    View this article via: PubMed Google Scholar
  19. Karschin A, Brockhaus J, Ballanyi K. KATP channel formation by the sulphonylurea receptors SUR1 with Kir6.2 subunits in rat dorsal vagal neurons in situ. J Physiol (Lond). 1998;509(Pt 2):339–346.
    View this article via: PubMed Google Scholar
  20. Miki T, et al. ATP-sensitive K+ channels in the hypothalamus are essential for the maintenance of glucose homeostasis. Nat Neurosci. 2001;4(5):507–512.
    View this article via: PubMed CrossRef Google Scholar
  21. Lee K, Dixon AK, Freeman TC, Richardson PJ. Identification of an ATP-sensitive potassium channel current in rat striatal cholinergic interneurones. J Physiol (Lond). 1998;510(Pt 2):441–453.
    View this article via: PubMed Google Scholar
  22. Liss B, Bruns R, Roeper J. Alternative sulfonylurea receptor expression defines metabolic sensitivity of K-ATP channels in dopaminergic midbrain neurons. EMBO J. 1999;18(4):833–846.
    View this article via: PubMed CrossRef Google Scholar
  23. Tricarico D, Mele A, Lundquist AL, Desai RR, George AL, Conte Camerino D. Hybrid assemblies of ATP-sensitive K+ channels determine their muscle-type-dependent biophysical and pharmacological properties. Proc Natl Acad Sci USA. 2006;103(4):1118–1123.
    View this article via: PubMed CrossRef Google Scholar
  24. Tran PT, Lee YH, Bhattarai JP, Park SJ, Yi HK, Han SK. Existence of ATP sensitive potassium currents on human periodontal ligament cells. Arch Oral Biol. 2017;76:48–54.
    View this article via: PubMed CrossRef Google Scholar
  25. Gu Y, Preston MR, El Haj AJ, Howl JD, Publicover SJ. Three types of K(+) currents in murine osteocyte-like cells (MLO-Y4). Bone. 2001;28(1):29–37.
    View this article via: PubMed CrossRef Google Scholar
  26. Koh SD, Bradley KK, Rae MG, Keef KD, Horowitz B, Sanders KM. Basal activation of ATP-sensitive potassium channels in murine colonic smooth muscle cell. Biophys J. 1998;75(4):1793–1800.
    View this article via: PubMed CrossRef Google Scholar
  27. Sim JH, et al. ATP-sensitive K(+) channels composed of Kir6.1 and SUR2B subunits in guinea pig gastric myocytes. Am J Physiol Gastrointest Liver Physiol. 2002;282(1):G137–G144.
    View this article via: PubMed CrossRef Google Scholar
  28. Nakayama S, et al. Sulphonylurea receptors differently modulate ICC pacemaker Ca2+ activity and smooth muscle contractility. J Cell Sci. 2005;118(Pt 18):4163–4173.
    View this article via: PubMed Google Scholar
  29. Livermore S, Piskuric NA, Salman S, Nurse CA. Developmental regulation of glucosensing in rat adrenomedullary chromaffin cells: potential role of the K(ATP) channel. Adv Exp Med Biol. 2012;758:191–198.
    View this article via: PubMed CrossRef Google Scholar
  30. Zhu Z, et al. Sulfonylurea receptor mRNA expression in pituitary macroadenomas. Endocrine. 1998;8(1):7–12.
    View this article via: PubMed CrossRef Google Scholar
  31. Teramoto N, et al. ATP-sensitive K+ channels in pig urethral smooth muscle cells are heteromultimers of Kir6.1 and Kir6.2. Am J Physiol Renal Physiol. 2009;296(1):F107–F117.
    View this article via: PubMed CrossRef Google Scholar
  32. Gopalakrishnan M, et al. Characterization of the ATP-sensitive potassium channels (KATP) expressed in guinea pig bladder smooth muscle cells. J Pharmacol Exp Ther. 1999;289(1):551–558.
    View this article via: PubMed Google Scholar
  33. Shorter K, Farjo NP, Picksley SM, Randall VA. Human hair follicles contain two forms of ATP-sensitive potassium channels, only one of which is sensitive to minoxidil. FASEB J. 2008;22(6):1725–1736.
    View this article via: PubMed CrossRef Google Scholar
  34. Leroy C, Dagenais A, Berthiaume Y, Brochiero E. Molecular identity and function in transepithelial transport of K(ATP) channels in alveolar epithelial cells. Am J Physiol Lung Cell Mol Physiol. 2004;286(5):L1027–L1037.
    View this article via: PubMed CrossRef Google Scholar
  35. Curley M, Cairns MT, Friel AM, McMeel OM, Morrison JJ, Smith TJ. Expression of mRNA transcripts for ATP-sensitive potassium channels in human myometrium. Mol Hum Reprod. 2002;8(10):941–945.
    View this article via: PubMed CrossRef Google Scholar
Version history
  • Version 1 (February 17, 2020): Electronic publication
  • Version 2 (March 2, 2020): Print issue publication
Advertisement
Advertisement