REVIE W A R T I C L E Open Access
channel in migraine
pathophysiology: a novel therapeutic target
Mohammad Al-Mahdi Al-Karagholi
, Jakob Møller Hansen
, Johanne Severinsen
, Inger Jansen-Olesen
and Messoud Ashina
Background: To review the distribution and function of K
channels, describe the use of K
in clinical trials and make the case that these channels may play a role in headache and migraine.
channels are widely present in the trigeminovascular system and play an important role in the
regulation of tone in cerebral and meningeal arteries. Clinical trials using synthetic K
channel openers report
headache as a prevalent-side effect in non-migraine sufferers, indicating that K
channel opening may cause
headache, possibly due to vascular mechanisms. Whether K
channel openers can provoke migraine in migraine
sufferers is not known.
Conclusion: We suggest that K
channels may play an important role in migraine pathogenesis and could be a
potential novel therapeutic anti-migraine target.
Keywords: Migraine, K
channels, Headache, Levcromakalim, Cromakalim
Adenosine 5′-triphosphate-sensitive K
openers have been used in clinical trials for the treatment
of hypertension and asthma. The most common side ef-
fect mentioned during treatment with K
openers was headache (62, 64, 66–79) (Tables 2 and 3).
However, only little attention has been focused on the role
channels in migraine pathophysiology.
channels were originally identified in cardiomyo-
cytes , but have also been found in several tissues, in-
cluding pancreatic α- and ß-cells, smooth muscle,
skeletal muscle and central neurons [2, 3]. The channels
belong to the family of inwardly rectifying K
that are inhibited at physiological intracellular levels
ATP/ADP ratio. When intracellular ATP is reduced
under conditions of metabolic challenges they open.
channels are critical in regulating insulin secretion,
controlling vascular tone, and protecting cells against
metabolic stress [2, 4, 5].
Over the past three decades, some preclinical evi-
dence has emerged indicating that K
play an important role in migraine pathophysiology.
In particular, the vasodilation effect of K
is relevant, since it is has been established that
endogenous neurotransmitters that trigger migraine
attacks are often associated with dilation of cranial
Here we review preclinical and clinical studies on
channels and discuss the K
channel as a novel
therapeutic target for migraine treatment.
Molecular structure and isoforms
channel is a hetero-octameric complex that
consists of four pore-forming K
(Kir) subunits and four regulatory sulfonylurea receptor
(SUR) subunits .
The Kir6.x subunit exists in two isoforms, Kir6.1 and
Kir6.2. The SUR subunit belongs to the ATP-binding
cassette (ABC) transporter family, regulated by
* Correspondence: firstname.lastname@example.org
Danish Headache Center, Department of Neurology, Rigshospitalet Glostrup,
Faculty of Health and Medical Sciences, University of Copenhagen, Nordre
Ringvej 57, DK-2600 Copenhagen, Denmark
Full list of author information is available at the end of the article
The Journal of Headache
© The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made.
Al-Karagholi et al. The Journal of Headache and Pain (2017) 18:90