Migraine: Calcium Channels and Glia

Abstract

Migraine is a common neurological disease that affects about 11% of the adult population. The disease is divided into two main clinical subtypes: migraine with aura and migraine without aura. According to the neurovascular theory of migraine, the activation of the trigeminovascular system (TGVS) and the release of numerous neuropeptides, including calcitonin gene-related peptide (CGRP) are involved in headache pathogenesis. TGVS can be activated by cortical spreading depression (CSD), a phenomenon responsible for the aura. The mechanism of CSD, stemming in part from aberrant interactions between neurons and glia have been studied in models of familial hemiplegic migraine (FHM), a rare monogenic form of migraine with aura. The present review focuses on those interactions, especially as seen in FHM type 1, a variant of the disease caused by a mutation in CACNA1A, which encodes the α1A subunit of the P/Q-type voltage-gated calcium channel.

Keywords: CACNA1A; CaV2.1; FHM; cortical spreading depression; glia; migraine.

Figure 1

Cortical spreading depression. Changes in central nervous system flow that may induce a migraine attack may be associated with the occurrence of spreading cortical spreading depression (CSD). Oligemia (reduced vascular flow) begins in the occipital and parieto-occipital areas, then moves through the cerebral cortex and stops at the medial and lateral sulcus. In some patients, CSD may extend to the frontal lobes. This phenomenon seems to be responsible for the aura formation during a migraine headache.

Figure 2

Induction of migraine attack due to sensitization of trigeminal ganglia and disturbed glutamatergic release. TRPA1 receptors in sensory neurons in trigeminal ganglia (TG) activate under environmental irritants taken by inhalation, ingestion or in an unknown mechanism. Activation of the TRPA1 receptor stimulates the release of calcitonin gene-related peptide (CGRP) that may enter bloodstream during migraine attack. CGRP receptor is expressed by majority on the neurons forming myelinated TG A-fibers, as well as on smooth muscles of dura’s vasculature. CGRP receptor stimulation increases blood flow. Besides CGRP, activated TG neurons secrete nitric oxide (NO). These mediators stimulate further the surrounding glial cells to produce interleukin-1β (IL-1β) that in turn leads to increased activity of cyclooxygenase (COX), associated with production of proinflammatory prostaglandin E2 (PGE2). This phenomenon may be one of foundations of the TG neurons sensitization. Subsequently, CGRP released by TG neurons may also promote release of tumor necrosis factor-α (TNF-α) in the glial satellite cells. That may cause a positive feedback loop of further TG-neuronal synthesis and secretion of CGRP. Furthermore, the released TNF-α may itself sensitize TG neurons and inflict overproduction of various other proinflammatory cytokines. Activation of TRPA channels increase the intracellular calcium ion levels (Ca²⁺), similarly to L-type of Voltage Gated Calcium Channel (CaV2.1). Mutations in CACNA1A gene lead to enhanced Ca²⁺ currents. The enhanced Ca²⁺ influx lead to excitation-inhibition imbalance and enhanced glutamate release. The interaction between glutamate and pre- and postsynaptic glutamate NMDA receptors (NMDAr) may facilitate the cortical spreading depression (CSD)—believed as one of the causes of migraine attack. Ca²⁺ channel blockers affect the CaV2.1 channels and reduce excessive Ca²⁺ influx to the cells, normalizing glutamate release and thus may be also used in the treatment of migraine headaches.

Figure 3

Locations of FHM1 mutations in the secondary structure of the calcium channel α2.1 subunit. 1—R192Q, 2—R195K, 3—S218L, 4—V581M, 5—R583Q, 6—T666M, 7—V714A, 8—D715E, 9—Y1246C, 10—K1336E, 11—R1347Q, 12—C1370Y, 13—Y1385C, 14—V1457L, 15—C1535S, 16—R1668W, 17—L1682P, 18—W1684R, 19—V1696I, 20—I1710T, 21—I1811L. I-IV- number of extracellular loop.