NBCel mutations and migraine

It has been known that pH in the brain shows rapid changes in response to electrical activity. These changes in local pH may have an important influence on neurobiological responses by modifying numerous enzymes, ion channels, transporters, and receptors [19].

Among several acid/base transporters expressed in the brain, NBCe1 is intensively expressed in olfactory bulb, hippocampal dentate gyrus, and cerebellum, localizing in both glial cells and neurons [56]. Although a large number of transporters may be involved in the pH homeostasis of the brain interstitial space, acid secretion by glial cells via inward electrogenic Na+-HCO3-cotransporter NBCe1B may have a significant role in the prevention of excessive neural activities. In fact, alkalosis in extracellular spaces is generally associated with enhanced neuronal excitability, while acidosis is known to suppress neural activity [19]. A recent study using NBCe1 knockout (KO) mice confirmed that NBCe1 mediates a depolarization-induced alkalinization (DIA) response in astrocytes [57]. This study revealed that NBCe1 also contributes partially to a DIA response in hippocampal neurons [57]. Bevensee et al. initially reported that the expression of NBCe1B is more abundant in astrocytes than in neuron, while NBCe1C show the reverse pattern of expression [18]. However, the expression of NBCe1C was also found in rat astrocytes [22]. Despite the intensive expression of NBCe1 in brain and the potential contribution of NBCe1 to the extracellular pH regulation in brain, the physiological significance of NBCe1 in brain had still remained speculative. However, recent work revealed an unrecognized association of migraine with NBCe1 mutations [10].

Migraine is a common, disabling, multifactorial disorder, affecting more than 10% of the population with women more affected than men [58]. Although genetic factor plays a substantial role in ordinary migraine, the genetic basis has been established only in familial hemiplegic migraine (FHM), a rare autosomal dominant subtype of migraine with aura. In addition to a similar headache phase as found in ordinarily migraine, FHM patients experience prolonged hemiparesis [59]. Thus far, three genes have been identified as the genetic basis for FHM: CACNA1A encoding the a1 subunit of voltage-gated neuronal Cav2.1 calcium channels [60], ATP1A2 encoding the a2 subunit of Na+/K+ ATPase [61], and SCN1A encoding the neuronal voltage-gated sodium channel Nav1.1 [62]. These mutations are thought to cause migraine by enhancing neuronal excitability [63].

We recently identified two sisters with pRTA, ocular abnormalities and hemiplegic migraine. Genetic analysis excluded pathological mutation in CACNA1A, ATP1A2, and SCN1A, but identified the homozygous S982NfsX4 mutation in the C-terminus of NBCe1 [10]. Several heterozygous members of the family also presented with glaucoma and migraine with or without aura. This mutant showed a normal electrogenic activity in Xenopus oocytes. When expressed in mammalian cells, however, the S982NfsX4 mutant showed almost no transport activity due to a predominant retention in the endoplasmic reticulum (ER). Several mutant proteins that are retained in the ER are known to exert a dominant negative effect by forming hetero-oligomer complexes with wild-type proteins [64], and NBCe1 can also form the oligomer complexes [65]. Indeed, co-expression analysis uncovered a dominant negative effect of the mutant through hetero-oligomer formation with wild-type NBCe1, which may be responsible for the occurrence of migraine and glaucoma in the heterozygous family members. To further substantiate NBCe1 mutations as a cause of migraine, we re-investigated the other pRTA pedigrees with distinct NBCe1 mutations, and found 4 additional homozygous patients with migraine: hemiplegic migraine with episodic ataxia in L522P [8], migraine with aura in N721TfsX29 [6], and migraine without aura in R510H and R881C [3,7]. Transient expression of GFP-tagged NBCe1B constructs carrying these mutations in C6 glioma cells revealed a remarkable coincidence between the apparent lack of membrane expression and the occurrence of migraine. From these and other results, we concluded that the near total loss of

NBCe1B activity in astrocytes can cause migraine potentially through dysregulation of synaptic pH [10]. We cannot exclude a possibility that the inactivation of NBCe1C is also involved in the pathogenesis of migraine.

Cerebral cortical hyperexcitability causing cortical spreading depression (CSD) seems to be the underlying pathophysiological mechanism of migraine aura [63]. In general, neuronal firing may lead to a rise in extracellular K+ concentration and further depolarization, but uptake of K+ into astrocytes can counteract this process. Therefore, enhanced neurotransmitter release by CACNA1A mutations, excessive neuronal firing by SCN1A mutations, or impaired clearance of K+ and/or glutamate by ATP1A2 mutations can all induce CSD [63].Neuronal excitation may also elicit an initial extracellular alkalosis, probably mediated by Ca2+/H+ exchange [19]. Upon depolarization, however, glial cells secret acid via inward electrogenic Na+-HCO3- cotransport NBCe1, i.e. DIA, overwhelming the initial extracellular alkalosis. Under normal condition, the net extracellular acidosis due to DIA makes surrounding neuronal cells less excitable, because protons suppress excitatory NMDA receptors, with a steep sensitivity in the physiological range of extracellular [19]. Absence of DIA due to defective membrane expression of NBCe1 in astrocytes may cause a positive feedback loop of increased neuronal activity leading to further NMDA-mediated neuronal hyperactivity, causing complete depolarization of a sizable population of brain cells, i.e. CSD. We therefore think that migraine associated with NBCe1 mutations represents a primary headache most likely caused by dysfunctional local pH regulation in the brain as shown in Figure 3.

Figure 3. Migraine-associated transporters. While SCN1A and CACNA1A may directly regulate neuron excitation, ATP1A2 may regulate neuron excitation indirectly via uptake of K+ and/or glutamate into astrocytes. On the other hand, NBCe1-mediated uptake of HCO3- into astrocytes may also regulate neuron excitation by affecting pH-sensitive NMDA receptors.

SCN1A

CACNA1A

Mutation Migraine

Figure 3. Migraine-associated transporters. While SCN1A and CACNA1A may directly regulate neuron excitation, ATP1A2 may regulate neuron excitation indirectly via uptake of K+ and/or glutamate into astrocytes. On the other hand, NBCe1-mediated uptake of HCO3- into astrocytes may also regulate neuron excitation by affecting pH-sensitive NMDA receptors.

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