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Local potassium signaling couples neuronal activity to vasodilation in the brain

Abstract

The mechanisms by which active neurons, via astrocytes, rapidly signal intracerebral arterioles to dilate remain obscure. Here we show that modest elevation of extracellular potassium (K+) activated inward rectifier K+ (Kir) channels and caused membrane potential hyperpolarization in smooth muscle cells (SMCs) of intracerebral arterioles and, in cortical brain slices, induced Kir-dependent vasodilation and suppression of SMC intracellular calcium (Ca2+) oscillations. Neuronal activation induced a rapid (<2 s latency) vasodilation that was greatly reduced by Kir channel blockade and completely abrogated by concurrent cyclooxygenase inhibition. Astrocytic endfeet exhibited large-conductance, Ca2+-sensitive K+ (BK) channel currents that could be activated by neuronal stimulation. Blocking BK channels or ablating the gene encoding these channels prevented neuronally induced vasodilation and suppression of arteriolar SMC Ca2+, without affecting the astrocytic Ca2+ elevation. These results support the concept of intercellular K+ channel–to–K+ channel signaling, through which neuronal activity in the form of an astrocytic Ca2+ signal is decoded by astrocytic BK channels, which locally release K+ into the perivascular space to activate SMC Kir channels and cause vasodilation.

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Figure 1: Kir channel currents in SMCs isolated from parenchymal arterioles.
Figure 2: Elevation of [K+]o to 10 mM dilates parenchymal arterioles and suppresses Ca2+ oscillations in arteriolar SMCs in brain slices.
Figure 3: Neuronal activity–induced dilation of arterioles is largely inhibited by blockers of Kir or BK channels in brain slices.
Figure 4: BK channel currents in astrocytic endfeet in brain slices.
Figure 5: Blockade of BK channels inhibits electrical stimulation–induced suppression of arteriolar smooth muscle Ca2+ oscillations in brain slices.
Figure 6: The absence of functional BK channels prevents electrical stimulation–induced suppression of Ca2+ oscillations in SMCs of parenchymal arterioles in brain slices.

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Acknowledgements

We thank D. Hill-Eubanks for comments on the manuscript and J. Brayden for help with the microelectrode recordings. This work was supported by the US National Institutes of Health (grants HL44455 and HL63722 to M.T.N. from the National Heart, Lung and Blood Institute), a postdoctoral fellowship from the American Heart Association (0425923T to J.A.F.), a National Institutes of Health training grant (HL07944 to M.K.W.), the Howard Hughes Medical Institute and the Totman Trust for Medical Research.

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Correspondence to Mark T Nelson.

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Supplementary information

Supplementary Fig. 1

Local K+ channel to K+ channel signaling between cells of the neurovascular unit mediates rapid neurovascular coupling. (PDF 39 kb)

Supplementary Video 1

Elevation of [K+]o to 10 mM dilates parenchymal arterioles in a cortical brain slice. (MOV 2619 kb)

Supplementary Video 2

ES-induced dilation of an arteriole in a brain slice. (MOV 2609 kb)

Supplementary Video 3

ES-induced dilation of an arteriole in a brain slice is prevented by inhibition of Kir channels. (MOV 2609 kb)

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Filosa, J., Bonev, A., Straub, S. et al. Local potassium signaling couples neuronal activity to vasodilation in the brain. Nat Neurosci 9, 1397–1403 (2006). https://doi.org/10.1038/nn1779

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