Vladimir Matchkov

TY - ABST

T1 - Mutation in the α2 isoform of Na,K-ATPase associated Familial Hemiplegic Migraine type 2 (FHM2) leads to elevated contractility and vasodilatation of cerebral arteries in mice

AU - Hangaard, Lise

AU - Lykke-Hartmann, Karin

AU - Xie, Zijian

AU - Aalkjær, Christian

AU - Matchkov, Vladimir

PY - 2014

Y1 - 2014

N2 - The vasogenic theory of migraine suggests that the aura (a phase preceding the headache and characterized by visual, sensory and/or motor disturbances) is associated with vasoconstriction-induced hypoxemia in the brain, while the subsequent headache is caused by a rebound vasodilation. FHM 2 is associated with few point mutations in the α2 isoform Na,K-ATPase. Mice bearing a mutation corresponding to the inherited mutation in FHM2 patients (G301R) were used in functional studies of middle cerebral arteries.Middle cerebral arteries from heterozygote G301R mice were not different in total α2 Na,K-ATPase mRNA in comparison with WT, but 51±11% of their mRNA contained G301R mutation. G301R mice had elevated blood pressure and unchanged heart rate. Inner diameter of cerebral arteries from G301R mice was significantly larger than in WT. G301R arteries were more sensitive and had higher maximal contraction to U46619, endothelin and K+-depolarization. This was associated with increased depolarization and sensitization to [Ca2+]i (in spite of reduced Ca2+ influx) in G301R arteries. pNaKtide, a peptide inhibiting the Na,K-ATPase-dependent Src activation, abolished differences between G301R and WT mice. In the presence of pNaKtide middle cerebral arteries from G301R and WT mice responded similarly by force, [Ca2+]i and membrane potential to agonist stimulation.G301R middle cerebral arteries have pronounced relaxation to elevated [K+]out in comparison with WT. This was associated with increased hyperpolarization of smooth muscles which was blocked by 30 µM BaCl2. BaCl2 abolished the difference in relaxations between the groups. G301R arteries had an elevated mRNA of inward rectifying K+ channels, 190±32% of the WT. In accordance with the vasogenic theory of migraine FHM2 associated mutation of the α2 Na,K-ATPase leads to both elevated contractility and increased relaxation of cerebral arteries. These abnormalities are, at least in part, mediated via disturbances in Src-kinase/Na,K-ATPase complex.

AB - The vasogenic theory of migraine suggests that the aura (a phase preceding the headache and characterized by visual, sensory and/or motor disturbances) is associated with vasoconstriction-induced hypoxemia in the brain, while the subsequent headache is caused by a rebound vasodilation. FHM 2 is associated with few point mutations in the α2 isoform Na,K-ATPase. Mice bearing a mutation corresponding to the inherited mutation in FHM2 patients (G301R) were used in functional studies of middle cerebral arteries.Middle cerebral arteries from heterozygote G301R mice were not different in total α2 Na,K-ATPase mRNA in comparison with WT, but 51±11% of their mRNA contained G301R mutation. G301R mice had elevated blood pressure and unchanged heart rate. Inner diameter of cerebral arteries from G301R mice was significantly larger than in WT. G301R arteries were more sensitive and had higher maximal contraction to U46619, endothelin and K+-depolarization. This was associated with increased depolarization and sensitization to [Ca2+]i (in spite of reduced Ca2+ influx) in G301R arteries. pNaKtide, a peptide inhibiting the Na,K-ATPase-dependent Src activation, abolished differences between G301R and WT mice. In the presence of pNaKtide middle cerebral arteries from G301R and WT mice responded similarly by force, [Ca2+]i and membrane potential to agonist stimulation.G301R middle cerebral arteries have pronounced relaxation to elevated [K+]out in comparison with WT. This was associated with increased hyperpolarization of smooth muscles which was blocked by 30 µM BaCl2. BaCl2 abolished the difference in relaxations between the groups. G301R arteries had an elevated mRNA of inward rectifying K+ channels, 190±32% of the WT. In accordance with the vasogenic theory of migraine FHM2 associated mutation of the α2 Na,K-ATPase leads to both elevated contractility and increased relaxation of cerebral arteries. These abnormalities are, at least in part, mediated via disturbances in Src-kinase/Na,K-ATPase complex.

M3 - Conference abstract for conference

T2 - Na, K-ATPase and Related Transport ATPases: Structure, Mechanism, Cell Biology, Health and Disease

Y2 - 30 August 2014 through 5 September 2014

ER -