Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2022 Aug 4;11(15):2406.
doi: 10.3390/cells11152406.

ATP-Sensitive Potassium Channels in Migraine: Translational Findings and Therapeutic Potential

Amalie Clement  1 , Song Guo  1   2 , Inger Jansen-Olesen  1 , Sarah Louise Christensen  1
Affiliations
Review

ATP-Sensitive Potassium Channels in Migraine: Translational Findings and Therapeutic Potential

Amalie Clement et al. Cells. .

Abstract

Globally, migraine is a leading cause of disability with a huge impact on both the work and private life of affected persons. To overcome the societal migraine burden, better treatment options are needed. Increasing evidence suggests that ATP-sensitive potassium (KATP) channels are involved in migraine pathophysiology. These channels are essential both in blood glucose regulation and cardiovascular homeostasis. Experimental infusion of the KATP channel opener levcromakalim to healthy volunteers and migraine patients induced headache and migraine attacks in 82-100% of participants. Thus, this is the most potent trigger of headache and migraine identified to date. Levcromakalim likely induces migraine via dilation of cranial arteries. However, other neuronal mechanisms are also proposed. Here, basic KATP channel distribution, physiology, and pharmacology are reviewed followed by thorough review of clinical and preclinical research on KATP channel involvement in migraine. KATP channel opening and blocking have been studied in a range of preclinical migraine models and, within recent years, strong evidence on the importance of their opening in migraine has been provided from human studies. Despite major advances, translational difficulties exist regarding the possible anti-migraine efficacy of KATP channel blockage. These are due to significant species differences in the potency and specificity of pharmacological tools targeting the various KATP channel subtypes.

Keywords: KATP channels; Kir6.x; SUR; glibenclamide; human migraine model; in vivo models; levcromakalim; migraine; provoked migraine.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the drafting, proofreading, and finalizing of the manuscript.

Figures

Figure 1
Figure 1
Simple structure of the KATP channel. (A) The Kir6.x subunit is composed of a two transmembrane region (TM1 and TM2) connected by a pore-forming region (H5). The SURx subunit is composed of three domains of either five transmembrane regions (TMD0) or six transmembrane regions (TMD1 and TMD2). The nucleotide binding domains are found intracellularly (NBD1 and NBD2). SUR2A and SUR2B only differ in their C-terminal end (C42). (B) The functional KATP channel is formed by four Kir6.x subunits and four SURx subunits (created using BioRender.com).
Figure 2
Figure 2
Molecular pathways and pharmacological agents leading to the opening of the KATP channel in vascular smooth muscle. The neuropeptides PACAP and CGRP activate KATP channels via the adenylyl cyclase pathway, while the NO donor GTN (glyceryl trinitrate) activates the channel via the guanylyl cyclase pathway. Cilostazol and Sildenafil are blockers of the phosphodiesterase 3 and 5 (PDE3 and PDE5), respectively, causing accumulation of cAMP and cGMP, which promote the opening of KATP channels. Levcromakalim causes vasodilation by direct action on the KATP channels (created using BioRender.com).
See this image and copyright information in PMC

References

    1. Steiner T.J., Stovner L.J., Jensen R., Uluduz D., Katsarava Z. Migraine Remains Second among the World’s Causes of Disability, and First among Young Women: Findings from GBD2019. J. Headache Pain. 2020;21:4–7. doi: 10.1186/s10194-020-01208-0. - DOI - PMC - PubMed
    1. James S.L., Abate D., Abate K.H., Abay S.M., Abbafati C., Abbasi N., Abbastabar H., Abd-Allah F., Abdela J., Abdelalim A., et al. Global, Regional, and National Incidence, Prevalence, and Years Lived with Disability for 354 Diseases and Injuries for 195 Countries and Territories, 1990–2017: A Systematic Analysis for the Global Burden of Disease Study 2017. Lancet. 2018;392:1789–1858. doi: 10.1016/S0140-6736(18)32279-7. - DOI - PMC - PubMed
    1. Olesen J. Headache Classification Committee of the International Headache Society (IHS) The International Classification of Headache Disorders, 3rd Edition. Cephalalgia. 2018;38:1–211. doi: 10.1177/0333102417738202. - DOI - PubMed
    1. Vgontzas A., Pavlović J.M. Sleep Disorders and Migraine: Review of Literature and Potential Pathophysiology Mechanisms. Headache. 2018;58:1030–1039. doi: 10.1111/head.13358. - DOI - PMC - PubMed
    1. Vuralli D., Ayata C., Bolay H. Cognitive Dysfunction and Migraine 17 Psychology and Cognitive Sciences 1701 Psychology 11 Medical and Health Sciences 1103 Clinical Sciences 11 Medical and Health Sciences 1109 Neurosciences. J. Headache Pain. 2018;19:109. doi: 10.1186/s10194-018-0933-4. - DOI - PMC - PubMed

Publication types