Abstract
Mutations in four genes have been identified in familial hemiplegic migraine (FHM), from which CACNA1A (FHM type 1) and SCN1A (FHM type 3) code for neuronal voltage-gated calcium or sodium channels, respectively, while ATP1A2 (FHM type 2) encodes the α2 isoform of the Na+,K+-ATPase's catalytic subunit, thus classifying FHM primarily as an ion channel/ion transporter pathology. FHM type 4 is attributed to mutations in the PRRT2 gene, which encodes a proline-rich transmembrane protein of as yet unknown function. The Na+,K+-ATPase maintains the physiological gradients for Na+ and K+ ions and is, therefore, critical for the activity of ion channels and transporters involved neuronal excitability, neurotransmitter uptake or Ca2+ signaling. Strikingly diverse functional abnormalities have been identified for disease-linked ATP1A2 mutations which frequently lead to changes in the enzyme's voltage-dependent properties, kinetics, or apparent cation affinities, but some mutations are truly deleterious for enzyme function and thus cause full haploinsufficiency. Here, we summarize structural and functional data about the Na+,K+-ATPase available to date and an overview is provided about the particular properties of the α2 isoform that explain its physiological relevance in electrically excitable tissues. In addition, current concepts about the neurobiology of migraine, the correlations between primary brain dysfunction and mechanisms of headache pain generation are described, together with insights gained recently from modeling approaches in computational neuroscience. Then, a survey is given about ATP1A2 mutations implicated in migraine cases as documented in the literature with focus on mutations that were described to completely destroy enzyme function, or lead to misfolded or mistargeted protein in particular model cell lines. We also discuss whether or not there are correlations between these most severe mutational effects and clinical phenotypes. Finally, perspectives for future research on the implications of Na+,K+-ATPase mutations in human pathologies are presented.
Highlights
ATP1A2 is a key player in K+ clearance, this aspect has been considered less important for the pathophysiology of migraine because the duration of the Cortical Spreading Depression (CSD) was not prolonged in the FHM type 2 (FHM2) mouse model (Leo et al, 2011). These findings collectively suggest that ATP1A2 mutations in migraine primarily cause a disorder of glutamatergic neurotransmission with defective regulation of the E/I balance in the brain (Pietrobon and Moskowitz, 2013)
The detailed atomic-scale understanding of ion transport and catalysis of the Na+,K+-ATPase provided by the wealth of structural data together with the multi-modal efforts of numerous experimentalists have provided a rather stringent concept of the effects of migraine-associated ATP1A2 mutations on molecular function
While the spectrum of functional disruptions matches the complexity of the Na+ pump’s inner workings and the enzyme’s even more complex integration into cellular signaling networks, the notion emerges that loss or change of any kind of functional parameter, including the seemingly subtle changes in voltage dependence could be of pathophysiological relevance
Summary
Functional studies of the ATP1A1 mutants showed loss of pump activity, strongly reduced K+ affinity and augmented inward proton leak currents (see section) at physiological potentials and concentrations of Na+ and K+ (Azizan et al, 2013).
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