Involvement of the Na⁺,K⁺‐ATPase isoforms in control of cerebral perfusion

Abstract

New Findings What is the topic of this review?In this review, we consider the role of the Na+,K+‐ATPase in cerebrovascular function and how it might be changed in familial hemiplegic migraine type 2 (FHM2). The primary focus is involvement of the Na+,K+‐ATPase isoforms in regulation of cerebrovascular tone. What advances does it highlight?In this review, we discuss three overall distinct mechanisms whereby the Na+,K+‐ATPase might be capable of regulating cerebrovascular tone. Furthermore, we discuss how changes in the Na+,K+‐ATPase in cerebral arteries might affect brain perfusion and thereby be involved in the pathology of FHM2. Abstract Familial hemiplegic migraine type 2 (FHM2) has been characterized by biphasic changes in cerebral blood flow during a migraine attack, with initial hypoperfusion followed by abnormal hyperperfusion of the affected hemisphere. We suggested that FHM2‐associated loss‐of‐function mutation(s) in the Na+,K+‐ATPase α2 isoform might be responsible for these biphasic changes in several ways. We found that reduced expression of the α2 isoform leads to sensitization of the contractile machinery to [Ca2+]i via Src kinase‐dependent signal transduction. This change in sensitivity might be the underlying mechanism for both abnormally potentiated vasoconstriction and exaggerated vasorelaxation. Moreover, the functional significance of the Na+,K+‐ATPase α2 isoform in astrocytes provides for the possibility of elevated extracellular potassium signalling from astrocytic endfeet to the vascular wall in neurovascular coupling.

Vascular microdomain signalling and possible novel treatments in cardiovascular diseases

“…Perivascular control of blood perfusion is especially important for the cerebral circulation, where its disturbances are associated with severe neuronal disorders and co‐morbid diseases. This was highlighted at the symposium by discussion of the changes in neurovascular signalling in association with migraine (Staehr, Rajanathan, & Matchkov, ). Cerebrovascular homeostasis was also addressed by discussion of the mechanisms involved in the regulation of interstitial fluid, i.e.…”

“…Staehr et al. () discuss the novel role of the old enzyme, the Na + ,K + ‐ATPase, in regulation of cerebral blood flow. The Na + ,K + ‐ATPase modulates vascular tone through multiple pathways, including an influence on membrane potential via its electrogenic activity, spatially restricted Na + ‐dependent Ca 2+ signalling and a novel ion‐transport‐independent signal transduction.…”

“…Accordingly, Staehr et al. () speculate that this might provide the mechanistic background for biphasic perfusion changes during a migraine attack characterized by initial hypoperfusion followed by hyperperfusion of the brain.…”

“…Early postnatal change in smooth muscle membrane transport and its potential modulation by perivascular nerves was discussed by Kostyunina, Gaynullina, Matchkov, and Tarasova (2019). Staehr et al (2019) discuss the novel role of the old enzyme, the Na + ,K + -ATPase, in regulation of cerebral blood flow. The Na + ,K + -ATPase modulates vascular tone through multiple pathways, including an influence on membrane potential via its electrogenic activity, spatially restricted Na + -dependent Ca 2+ signalling and a novel ion-transport-independent signal transduction.…”

“…The Na + ,K + -ATPase modulates vascular tone through multiple pathways, including an influence on membrane potential via its electrogenic activity, spatially restricted Na + -dependent Ca 2+ signalling and a novel ion-transport-independent signal transduction. Staehr et al (2019) proposed exclusive importance of this Src-kinase-dependent signal transduction for the cerebral circulation, where it, along with other targets, modulates the sensitivity of contractile machinery for intracellular Ca 2+ . This is mediated through phosphorylation of the regulatory myosin phosphatase targeting protein, which in turn affects cerebrovascular diameter (Staehr et al, 2019).…”