Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • Vascular Malformations (Apr 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
Top
  • View PDF
  • Download citation information
  • Send a comment
  • Terms of use
  • Standard abbreviations
  • Need help? Email the journal
  • Top
  • Physiological roles for cardiac KATP channels
  • Open questions
  • Footnotes
  • References
  • Version history
  • Article usage
  • Citations to this article

Advertisement

Commentary Free access | 10.1172/JCI16122

The surprising role of vascular KATP channels in vasospastic angina

Eduardo Marbán

Institute of Molecular Cardiobiology, Johns Hopkins University, Baltimore, Maryland 21205, USA.

Phone: (410) 955-2776; Fax: (410) 955-7953; E-mail: marban@jhmi.edu.

Find articles by Marbán, E. in: PubMed | Google Scholar

Published July 15, 2002 - More info

Published in Volume 110, Issue 2 on July 15, 2002
J Clin Invest. 2002;110(2):153–154. https://doi.org/10.1172/JCI16122.
© 2002 The American Society for Clinical Investigation
Published July 15, 2002 - Version history
View PDF

The golden age of single-channel electrophysiology was punctuated by the discovery of a curious class of potassium-selective channels in the surface membranes of heart cells (1, 2). These channels, silent under normal metabolic conditions, become robustly active when submembrane ATP is depleted. The opening of such KATP channels was soon recognized to underlie the loss of cellular excitability during metabolic stress (3, 4) and (later, in an in vivo correlate) to mediate the so-called ST segment elevation, an electrocardiographic change diagnostic of transmural injury during prolonged coronary ischemia (5). While these channels were discovered in heart cells, they are broadly-distributed throughout the body; their most obvious physiological role is in the pancreas, where they transduce changes in glucose concentration into alterations of β cell excitation and insulin secretion (6). Ironically, the role of KATP channels in the heart, where they were first discovered, remains mysterious. In the present issue and in recent work published elsewhere, new surprises emerge regarding the identities and the roles of KATP channels in the vasculature.

The general molecular structure of KATP channels was clarified by the pioneering work of the Bryan, Aguilar-Bryan (7) and Seino laboratories (8). KATP channels turn out to be complex hetero-octamers of four subunits encoded by sulfonylurea receptor (Sur) genes, surrounding a central pore made up of four Kir6-encoded K channel subunits (9). Different tissues express different permutations of the three possible Surs (Sur1, and the Sur2 splice variants, Sur2A and Sur2B) and two pore-forming subunits (Kir6.1 and Kir6.2). The conventional surface KATP channels in the heart are formed by Sur2 and Kir6.2, whereas those in pancreatic β cells consist of Sur1 and Kir6.2. KATP channels have a rich pharmacology (10), including a number of venerable vasodilators (e.g., the KATP channel agonists diazoxide and minoxidil) and anti-diabetic agents (notably the KATP channel blocker glybenclamide), which were in clinical use long before their targets were recognized.

Physiological roles for cardiac KATP channels

KATP channels have received much attention recently due to two related puzzles. First, a spirited controversy rages regarding the role of KATP channels in cardioprotection against ischemia. Drugs that open KATP channels clearly confer resistance to ischemia, while blockers prevent the development of ischemic preconditioning (11). The controversy lies in the mechanism of the cardioprotection and in the precise identity of the channels responsible. Much evidence points to mitochondria as the site of action (11), but the mitochondrial site of action came into question when Kir6.2 knockout mice were found to lack surface, but not mitochondrial KATP channels, and to be resistant to ischemic preconditioning (12).

The second puzzle surrounded the physiological role of the Kir6.1 subunit, which is found in many tissues at the mRNA and protein levels. Little was known about Kir6.1 until it was recently knocked-out by Miki and coworkers (13). The loss of Kir6.1 produced a dramatic, discrete phenotype: The mice developed spontaneous bouts of coronary vasospasm and ST elevation, which often proved fatal due to conduction block. These mice reproduced key features of vasospastic or Prinzmetal angina, a syndrome of sudden coronary vasoconstriction without underlying atherosclerosis. Vascular smooth muscle cells from Kir6.1 knockout mice were found to have no detectable KATP currents and to lack all vasodilatory responses to KATP channel agonists.

In the present issue, Chutkow et al. (14) further clarify the identity of vascular smooth muscle KATP channels by showing that Sur2 knockout mice also develop a Prinzmetal phenotype and loss of KATP channels in vascular muscle, while manifesting the expected lack of KATP currents in cardiac cells. The inescapable conclusion of these two studies (13, 14) is that the KATP channels of vascular smooth muscle consist of one or another splice variant of Sur2 along with Kir6.1. That particular combination of subunits thus represents a promising target for the development of novel anti-anginal compounds. The new results give reason to wonder whether nicorandil, a remarkably effective anti-anginal drug commonly used in Japan and Europe (but sadly absent from the US pharmacopeia), might preferentially activate Sur2 and Kir6.1 channels.

Open questions

The concordant findings between these two recent papers raise a number of critical questions and leave others unanswered. Some of these relate to the relationships among known K+ channels. For instance, are the vascular KATP channels that disappear with knockout of Sur2 or Kir6.1 truly conventional KATP channels, or might they be identical to the previously described nucleotide diphosphate–sensitive (KNDP) channels (15)? More extensive characterization of the pharmacological and single-channel properties of the wild-type channels will be required to sort out this question. Likewise, the identity of the mitochondrial KATP channels that have been implicated in cardiac preconditioning remains in doubt. Miki et al. argue that mitochondrial KATP channels are not encoded by Kir6.1, as evidenced by a preserved mitochondrial flavoprotein response to the cardioprotective KATP channel agonist diazoxide (13). Since flavoprotein responses also remain intact in Kir6.2 knockout mice (12), it may be that neither of these subunits contributes to the channel activity found in mitochondria. Indeed, a role for Sur2, the known partner for Kir6.2 in cardiac tissue, seems unlikely, based on the distinctive pharmacological profile of mitochondrial KATP channels (10), but direct tests in the present knockouts would provide additional welcome information.

It is also unclear, given the wide distribution of KATP channels throughout the vasculature, why Kir6.1 and Sur2 knockout mice exhibit a primary coronary phenotype. Coronary vessels may be unusually prone to episodic vasoconstriction, but it remains to be seen if a similar pattern of events might occur in other organs — although perhaps with relatively benign effects. However, perhaps the most urgent clinical question to arise from this work concerns how faithfully the two models reproduce human Prinzmetal angina. The sex distribution of affected mice in the present report (14) does not mirror the female preponderance in humans. Moreover, conduction disturbances and sudden death are not typical features of the clinical syndrome. Do these terminal events arise simply from the severity of ischemia, or does the knockout of KATP channels per se confer susceptibility to unstable cardiac impulse transmission? Additional studies with pharmacological vasoconstrictors in wild-type mice, along the lines of those reported by Miki et al. (13), would presumably help in sorting out this important question.

Footnotes

See the related article beginning on page 203.

References
  1. Noma, A. ATP-regulated K+ channels in cardiac muscle. Nature 1983. 305:147-148.
    View this article via: PubMed CrossRef Google Scholar
  2. Trube, G, Hescheler, H. Inward-rectifying channels in isolated patches of the heart cell membrane: ATP-dependence and comparison with cell-attached patches. Pflugers Arch 1984. 401:178-184.
    View this article via: PubMed CrossRef Google Scholar
  3. Nichols, CG, Lopatin, AN. Inward rectifier potassium channels. Annu Rev Physiol 1997. 59:171-191.
    View this article via: PubMed CrossRef Google Scholar
  4. O’Rourke, B, Ramza, BM, Marban, E. Oscillations of membrane current and excitability driven by metabolic oscillations in heart cells. Science 1994. 265:962-966.
    View this article via: PubMed CrossRef Google Scholar
  5. Li, RA, Leppo, M, Miki, T, Seino, S, Marbán, E. Molecular basis of electrocardiographic ST-segment elevation. Circ Res 2000. 87:837-839.
    View this article via: PubMed Google Scholar
  6. Ashcroft, FM, Gribble, FM. ATP-sensitive K+ channels and insulin secretion: their role in health and disease. Diabetologia 1999. 42:903-919.
    View this article via: PubMed CrossRef Google Scholar
  7. Aguilar-Bryan, L, et al. Cloning of the beta cell high-affinity sulfonylurea receptor: a regulator of insulin secretion. Science 1995. 268:423-426.
    View this article via: PubMed CrossRef Google Scholar
  8. Inagaki, N, et al. Reconstitution of IKATP: an inward rectifier subunit plus the sulfonylurea receptor. Science 1995. 270:1166-1170.
    View this article via: PubMed CrossRef Google Scholar
  9. Clement (IV), JP, et al. Association and stoichiometry of K(ATP) channel subunits. Neuron 1997. 18:827-838.
    View this article via: PubMed CrossRef Google Scholar
  10. Liu, Y, Ren, G, O’Rourke, B, Marbán, E, Seharaseyon, J. Pharmacological comparison of native mitochondrial K(ATP) channels with molecularly defined surface K(ATP) channels. Mol Pharmacol 2001. 59:225-230.
    View this article via: PubMed Google Scholar
  11. Liu, E, et al. Mitochondrial ATP-dependent potassium channels. Viable candidate effectors of ischemic preconditioning. Ann NY Acad Sci 1999. 874:27-37.
    View this article via: PubMed CrossRef Google Scholar
  12. Suzuki, M, et al. Role of sarcolemmal K(ATP) channels in cardioprotection against ischemia/reperfusion injury in mice. J Clin Invest 2002. 109:509-516. doi:10.1172/JCI200214270.
    View this article via: JCI PubMed Google Scholar
  13. Miki, T, et al. Mouse model of Prinzmetal angina by disruption of the inward rectifier Kir6.1. Nat Med 2002. 8:466-472.
    View this article via: PubMed CrossRef Google Scholar
  14. Chutkow, WA, et al. Episodic coronary artery vasospasm and hypertension develop in the absence of Sur2 KATP channels. J Clin Invest 2002. 110:203-208. doi:10.1172/JCI200215672.
    View this article via: JCI PubMed Google Scholar
  15. Fujita, A, Kurachi, Y. Molecular aspects of ATP-sensitive K+ channels in the cardiovascular system and K+ channel openers. Pharmacol Ther 2000. 85:39-53.
    View this article via: PubMed CrossRef Google Scholar
Version history
  • Version 1 (July 15, 2002): No description

Article tools

  • View PDF
  • Download citation information
  • Send a comment
  • Terms of use
  • Standard abbreviations
  • Need help? Email the journal

Metrics

  • Article usage
  • Citations to this article

Go to

  • Top
  • Physiological roles for cardiac KATP channels
  • Open questions
  • Footnotes
  • References
  • Version history
Advertisement
Advertisement

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts