Migraine is a dysfunction of neuronal potassium ion channels

Abstract

Migraine is a primary headache disorder characterized by unilateral pain usually with aura, that affects approximately one in six individuals in India. The underlying biomechanical processes of migraine are still poorly understood, and new research is constantly being published. One of the major factors in migraine pathogenesis is the dysfunction of ion channels in the trigeminal nuclei and sensory cortices. Potassium channels are modulators and regulators of neuronal signaling and conductance, playing an important role in maintenance of the membrane potential and neuronal conduction. Therefore, potassium channel dysfunctions are potential factors in migraine pathogenesis, and thus targets for specific antimigraine prophylaxis. This review reveals that potassium channels play a significant role in pathogenesis and management of migraine. Dysfunctions in K_ATP channels, K_2P channels including TRESK and TREK-1, small and large conductance calcium-sensitive potassium channels (SK_Ca and BK_Ca), and voltage-gated potassium channels (K_V) are known to affect the incidence and progression of migraine in the general populace. K_ATP openers can induce migraine like phenotype, but K_ATP blockers have so far not been effective in reducing the intensity of migraine headache. Potassium channels are a potential druggable target for migraine prophylaxis with several compounds currently in preclinical trials.

Keywords: acrylamide (S-1); druggable targets; glibenclamide; levcromakalim; migraine; potassium channels.

Figure 1

Mechanisms of migraine—environmental triggers and genetic predisposition result in cortical spreading depression, which has three effects: irregular activation of cortices, which results in aura and sensitivity to senses; and triggering of trigeminal nerves and increased permeability of blood–brain barrier, which result in pain due to vasodilation and sterile inflammation.

Figure 2

Flowchart showing the retrieval, screening, and assessment process for the review generated using the web tool PRISMA2020 (183).

Figure 3

ATP-sensitive KIR6.1 function. (A) Depicts the deactivation trigger: the presence of adenosine triphosphate near the cell interior region of the channel protein prevents potassium transport; and (B) depicts the activation trigger: the absence of adenosine diphosphate near the cell interior region of the channel protein allows potassium transport.

Figure 4

Protein model of KIR6.2 tetramer. The molecule is oriented such that the cytosolic region falls to the left of the manuscript. The two surfaces of the cell membrane are denoted by two black bars. Image modified from Martin et al. (184) as retrieved from the RCSB Protein Data Bank.

Figure 5

TREK-1 function. (A) Depicts the normal function: open rectification where the ions flow according to the charge gradient, whereas (B) depicts the altered function upon phosphorylation, where change in membrane voltage switches the channel between open and closed.

Figure 6

Open rectifier function. TRESK, TASK, TREK-2, and TRAAK are all open rectifiers, which allow free flow of potassium ions both ways across the plasma membrane.

Figure 7

Protein model of TASK-2 channel (K2P5.1) dimer. The molecule is oriented such that the cytosolic region falls to the left of the manuscript. The two surfaces of the cell membrane are denoted by two black bars. Image modified from Li et al. (185) as retrieved from the RCSB Protein Data Bank.

Figure 8

Large conductance calcium-gated potassium channel function. These channels regulate membrane depolarization by pushing potassium channels into the extracellular space.

Figure 9

Small conductance calcium-gated potassium channel function. These channels regulate membrane depolarization by pushing potassium channels into the extracellular space.

Figure 10

Voltage gated potassium channel family 7 function. KV7.2, 7.3, and 7.5 can heteromerize with each other to regulate the exact threshold voltage that opens the channel. These produce the slow-activating M current in the brain.

Figure 11

Protein model of BKCa channel (KCa1.1) tetramer. The molecule is oriented such that the cytosolic region falls to the left of the manuscript. The two surfaces of the cell membrane are denoted by two black bars. Image modified from Tao et al. (186) as retrieved from the RCSB Protein Data Bank.

Figure 12

Protein model of KV7.1 tetramer. The molecule is oriented such that the cytosolic region falls to the left of the manuscript. The two surfaces of the cell membrane are denoted by two black bars. Image modified from Ma et al. (187) as retrieved from the RCSB Protein Data Bank.

Figure 13

Mind map showing the subtypes of potassium channels. The root node, labelled ‘Potassium Channels’, is light-blue. There are three subtypes of potassium channels, shown as gray nodes. The families are shown as green nodes for families not implicated in migraine, and orange nodes for families implicated in migraine literature.