The KATP channel in migraine pathophysiology: a novel therapeutic target for migraine

Abstract

Background: To review the distribution and function of K_ATP channels, describe the use of K_ATP channels openers in clinical trials and make the case that these channels may play a role in headache and migraine.

Discussion: K_ATP 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_ATP channel openers report headache as a prevalent-side effect in non-migraine sufferers, indicating that K_ATP channel opening may cause headache, possibly due to vascular mechanisms. Whether K_ATP channel openers can provoke migraine in migraine sufferers is not known.

Conclusion: We suggest that K_ATP channels may play an important role in migraine pathogenesis and could be a potential novel therapeutic anti-migraine target.

Keywords: Cromakalim; Headache; KATP channel; KATP channels; Levcromakalim; Migraine.

Fig. 1

Molecular structure and isoforms. a Two major Kir6.x isoforms (Kir6.1 and Kir 6.2) and three major SUR isoforms (SUR1, SUR2A and SUR 2B) have been identified. b Kir.x subunits combine tissue-specifically with different SUR subunits to form various native K_ATP channels. Pancreatic, cardiac and smooth muscle K_ATP channels are made up of Kir6.2/SUR1, Kir6.2/SUR2A and Kir6.1 (or Kir6.2)/SUR2B, respectively [2]. Kir, inwardly rectifying K⁺ channels; SUR, sulfonylurea receptor

Fig. 2

Schematic diagram of the K_ATP channel. Kir6.x subunits have two transmembrane domains, and a large cytoplasmic domain including an inhibitory binding site for ATP [8, 84]. SUR subunits have many transmembrane domains and two intracellular nucleotide binding domains (NBD1 and NBD2), which stimulate opening of the channel after binding to MgADP [85]

Fig. 3

Opening of vascular ATP sensitive K channels. Endogenous molecules (ATP, cAMP and cGMP) and exogenous pharmacological agents (cromakalim and glibenclamide) regulate the activity of K_ATP channels, which help controlling the vascular tone

Fig. 4

Signaling pathways through vascular smooth muscle K_ATP channels. Numerous endogenous vasodilators activate vascular smooth muscle K_ATP channels through adenylate cyclase and PKA phosphorylation. Conversely, endogenous vasoconstrictors inhibit vascular smooth muscle K_ATP channels through DAG and PKC phosphorylation. CGRP, calcitonin gene-related peptide; PGI₂, prostaglandin I₂; VIP, vasoactive intestinal peptide; AngII, angiotensin II; NPY, neuropeptide Y; NA, noradrenaline; 5-HT, 5-hydroxytryptamine; Gs, G-protein-coupled receptor alpha stimulation; Gi, G-protein-coupled receptor alpha i/q; DAG, diacylglycerol; PKA and PKC, protein kinase A and C, respectively