ATP1A2 Mutations in Migraine: Seeing through the Facets of an Ion Pump onto the Neurobiology of Disease

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.

The α2β2 isoform combination dominates the astrocytic Na+/K+-ATPase activity and is rendered nonfunctional by the α2.G301R familial hemiplegic migraine type 2-associated mutation

“…This severe autosomal form of migraine with aura is associated with hemiparesis and sometimes accompanied by manifestations such as epilepsy, seizures, anxiety, compulsive disorder, and developmental disabilities (Bottger et al, 2012;Pietrobon, 2007;Segall et al, 2005). More than 60 human ATP1A2 mutations are linked to FHM2 (reviewed in Friedrich, Tavraz, & Junghans, 2016), amongst these a mutation at amino acid residue 301 (G!R), observed in two independent Italian families with several members suffering from hemiplegic migraine attacks (Santoro et al, 2011;Spadaro et al, 2004). Heterozygous knock-in mice harboring the Atp1a2 disease mutations G301R (Bottger et al, 2016) and W887R (Leo et al, 2011) were generated as animal models of FHM2.…”

Diffusion behavior of the fluorescent proteins eGFP and Dreiklang in solvents of different viscosity monitored by fluorescence correlation spectroscopy

“…In a preceding paper, we had explored the use of DRK for monitoring the diffusion behavior of plasma membrane-embedded proteins by FCS using FP-labeled Na,K-ATPase expressed in human embryonal kidney (HEK293) cells [9]. Na,K-ATPase is a 160 kDa plasma membrane ion transporter [10], which requires interactions with cellular matrix or cytoskeletal proteins for proper targeting, and these interactions should profoundly influence the diffusion behavior of the transporter in the cell membrane [9]. We found that the autocorrelation function of DRK-labelled Na,K-ATPase molecules expressed at the plasma membrane of HEK 293 cells showed significantly shortened diffusion times compared to eGFP-labeled Na,K-ATPase, although the diffusion times of purified or cytoplasmically expressed DRK were not different from those of eGFP [9].…”

Disruption of ankyrin B and caveolin-1 interaction sites alters Na+,K+-ATPase lateral diffusion in HEK293 cell plasma membranes

“…Different isoforms combine to form Na + ,K + -ATPase isozymes with distinct kinetic properties, which are regulated in a tissue-and developmental-specific manner. Within the same cell, more than one isoform can be expressed at the same time, and regulatory mechanisms have been developed by evolution to adjust the isoforms' expression and activity to fulfill the particular physiological requirements (Friedrich et al, 2016).…”

“…This highlights the Na + ,K + -ATPase as a paramount target for neurological disorders and has stimulated research on structure-function relationships, regulation and pharmacological interference of this important enzyme. A recent review about the involvement of the Na + ,K + -ATPase α 2 -subunit in FHM2 and the effects of disease-related mutations can be found in (Friedrich et al, 2016).…”

“…Whereas most mutations identified in FHM2 (and RDP or AHC as well) lead to distinct functional changes of the Na + ,K + -ATPase that frequently support the notion of loss-of-function effects, several FHM2 mutations fail to exhibit functional alterations when assayed in a particular cell type (Tavraz et al, 2008). Thus, in order to completely address all possible reasons for pathophysiological consequences of Na + ,K + -ATPase mutations in humans, functional studies must not only include electrophysiological and biochemical experiments in various relevant cell models, but should also assess effects regarding cellular quality control mechanisms, α/β subunit assembly, plasma membrane targeting, protein degradation, protein phosphorylation and -importantly -interactions with other proteins that might interfere with the aforementioned processes (Friedrich et al, 2016).…”