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 (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.

Pharmacological Profiling of KATP Channel Modulators: An Outlook for New Treatment Opportunities for Migraine

“…The existing treatments with triptans and non-selective prophylactic drugs are insufficient, and even with the recent advent of small molecule CGRP receptor antagonists and human monoclonal antibodies against CGRP or its receptor, despite representing a major advance, there is still a need for additional or better treatment options [ 3 , 4 ]. A target for such a treatment option could be the vascular ATP-sensitive potassium (K ATP ) channel because it is expressed in migraine relevant tissues and dilates cephalic blood vessels [ 5 ]. Dilation of the dural vasculature, and especially the middle meningeal artery (MMA), has been implicated as one component underlying migraine.…”

Identification of Novel Alkaloids from Portulaca oleracea L. and Characterization of Their Pharmacokinetics and GLP-1 Secretion-Promoting Activity in STC-1 Cells

“…As for the other two pairs ( 1 and 2 ; 3 and 4 ), the R -configuration appeared to be more effective at triggering the release of intracellular Ca 2+ , consistent with the result from molecular docking. The ability of these compounds to trigger a release of intracellular Ca 2+ concentration was attributed to their binding with SUR1, which led to the closure of K ATP channels and the eventual opening of the Ca 2+ channels, causing an influx of Ca 2+ …”

“…The ability of these compounds to trigger a release of intracellular Ca 2+ concentration was attributed to their binding with SUR1, which led to the closure of K ATP channels and the eventual opening of the Ca 2+ channels, causing an influx of Ca 2+ . 39 Journal of Agricultural and Food Chemistry In STC-1 cells, a rise in intracellular Ca 2+ caused by the closure of K ATP channels following the binding of a compound to SUR1 is expected to result in the secretion of GLP-1, and the extent of GLP-1 release should parallel the magnitude of the rise in intracellular Ca 2+ . Only STC-1 cells treated with compound 3 exhibited significantly (P < 0.05) higher GLP-1 secretion (134.82 ± 0.64%) than those treated with nateglinide.…”

Exploring Novel Therapeutic Targets in the Common Pathogenic Factors in Migraine and Neuropathic Pain

“…More clinical research on targeting TRP ion channels is awaited to be know the potential use of TRP receptor modulators for those subtypes. In addition, ATP-sensitive potassium channels are of particular interest for their roles and potential targets in migraine treatment [ 228 ].…”