Targeting BK_Ca Channels in Migraine: Rationale and Perspectives

Large (big)-conductance calcium-activated potassium (BK_Ca) channels are expressed in migraine-related structures such as the cranial arteries, trigeminal ganglion and trigeminal spinal nucleus, and they play a substantial role in vascular tonus and neuronal excitability. Using synthetic BK_Ca channels openers was associated with headache as a frequent adverse effect in healthy volunteers. Additionally, BK_Ca channels are downstream molecules in migraine signalling pathways that are activated by several compounds known to provoke migraine, including calcitonin gene-related peptide (CGRP), pituitary adenylate cyclase-activating polypeptide (PACAP) and glyceryl trinitrate (GTN). Also, there is a high affinity and a close coupling between BK_Ca channels and ATP-sensitive potassium (K_ATP) channels, the role of which has recently been established in migraine pathophysiology. These observations raise the question as to whether direct BK_Ca channel activation can provoke migraine in migraine patients, and whether the BK_Ca channel could be a potential novel anti-migraine target. Hence, randomized and placebo-controlled clinical studies on BK_Ca channel openers or blockers in migraine patients are needed.