The α2 Isoform of Na,K‐ATPase Modulates Vascular Tone via Activation of Src kinase (Src) Signaling Pathway: a Lesion from Mouse Model for Familial Hemiplegic Migraine Type 2 (FHM2).

The vasogenic theory of migraine suggests that the aura is associated with vasoconstriction‐induced hypoxemia in the brain, while the subsequent headache is caused by a rebound vasodilation. FHM2 is associated with inherited point mutations (including G301R) in the α2 isoform Na,K‐ATPase. Vascular function of wild type (WT) and heterozygotes mice bearing G301R+/‐ mutation was compared. G301R+/‐ mice had normal blood pressure (BP) but an increased BP response to stress compared to WT mice. There was no difference in contractile responses of mesenteric small arteries from G301R+/‐ and WT. Middle cerebral artery (MCA) diameter was larger in arteries from G301R+/‐ compared to WT and constricted stronger to U46619, endothelin and K + ‐depolarization. This was associated with increased depolarization and sensitization to [Ca 2+ ] i . pNaKtide, a peptide inhibiting the Na,K‐ATPase‐dependent Src activation, abolished differences between G301R+/‐ and WT. G301R+/‐ MCAs hyperpolarized and relaxed more elevated [K + ] out than MCAs from WT mice. These responses were Ba 2+ sensitive. G301R+/‐ arteries had elevated mRNA for inward rectifying K + channels; 190±32% of the WT. FHM2‐associated mutation of the α2 Na,K‐ATPase leads to both elevated contractility and increased relaxation of cerebral arteries. These abnormalities are mediated via disturbances in Src‐kinase/Na,K‐ATPase complex and expression of inward rectifying K + channels, respectively. This signaling has more significant role in cerebral than in peripheral circulation.