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

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 (K_ATP) channels are involved in migraine pathophysiology. These channels are essential both in blood glucose regulation and cardiovascular homeostasis. Experimental infusion of the K_ATP 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 K_ATP channel distribution, physiology, and pharmacology are reviewed followed by thorough review of clinical and preclinical research on K_ATP channel involvement in migraine. K_ATP 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 K_ATP channel blockage. These are due to significant species differences in the potency and specificity of pharmacological tools targeting the various K_ATP channel subtypes.

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

Figure 1

Simple structure of the K_ATP 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 K_ATP channel is formed by four Kir6.x subunits and four SURx subunits (created using BioRender.com).

Figure 2

Molecular pathways and pharmacological agents leading to the opening of the K_ATP channel in vascular smooth muscle. The neuropeptides PACAP and CGRP activate K_ATP 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 K_ATP channels. Levcromakalim causes vasodilation by direct action on the K_ATP channels (created using BioRender.com).