Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2015 Mar;14(3):258-67.
doi: 10.1016/j.autrev.2014.11.010. Epub 2014 Nov 22.

Regulation of neurovascular coupling in autoimmunity to water and ion channels

Peter Jukkola  1 , Chen Gu  2
Affiliations
Review

Regulation of neurovascular coupling in autoimmunity to water and ion channels

Peter Jukkola et al. Autoimmun Rev. 2015 Mar.

Abstract

Much progress has been made in understanding autoimmune channelopathies, but the underlying pathogenic mechanisms are not always clear due to broad expression of some channel proteins. Recent studies show that autoimmune conditions that interfere with neurovascular coupling in the central nervous system (CNS) can lead to neurodegeneration. Cerebral blood flow that meets neuronal activity and metabolic demand is tightly regulated by local neural activity. This process of reciprocal regulation involves coordinated actions of a number of cell types, including neurons, glia, and vascular cells. In particular, astrocytic endfeet cover more than 90% of brain capillaries to assist blood-brain barrier (BBB) function, and wrap around synapses and nodes of Ranvier to communicate with neuronal activity. In this review, we highlight four types of channel proteins that are expressed in astrocytes, regarding their structures, biophysical properties, expression and distribution patterns, and related diseases including autoimmune disorders. Water channel aquaporin 4 (AQP4) and inwardly rectifying potassium (Kir4.1) channels are concentrated in astrocytic endfeet, whereas some voltage-gated Ca(2+) and two-pore domain K(+) channels are expressed throughout the cell body of reactive astrocytes. More channel proteins are found in astrocytes under normal and abnormal conditions. This research field will contribute to a better understanding of pathogenic mechanisms underlying autoimmune disorders.

Keywords: Astrocyte; Autoimmunity; Blood–brain barrier; Ion channel; Neurovascular coupling; Water channel.

PubMed Disclaimer

Figures

Figure 1
Figure 1. Astrocytes in neurovascular units in white and gray matter
(A) Axons (YFP in green in merged), astrocytes (GFAP staining in blue in merged) and astrocytic endfeet (AQP4 staining in red in merged) in spinal cord white matter. The white arrow, a putative node of Ranvier. (B) Neurovascular units in cortical gray matter. Axons, dendrites and dendritic spines are in green. White arrowheads, dendritic spines. (C) Neurovascular units in cortical gray matter at the peak stage of EAE (Experimental Autoimmune Encephalomyelitis). These sections were from Thy1:YFP transgenic mice. Confocal image stacks (40 µm in thickness) were collapsed into 2D images. These images are modified from our recent paper [159].
Figure 2
Figure 2. Structure and function of channel proteins highly concentrated in astrocytic endfeet
(A) AQP4 structural diagram, showing eight membrane-embedded helical segments. Met1 and Met23 (black) are the translation initiation sites for the two AQP4 splice variants, M1 and M23. Residues highlighted in purple, green, and blue in the N-terminus are involved in regulating formation of orthogonal arrays of AQP4 tetramers. The AQP4 C-terminus contains a PDZ domain (in green) [reproduced from [42]]. (B) Osmotic water permeability of astroglial cells in AQP4 KO mice and in wildtype mice with and without AQP4 RNAi treatment. Changes in calcein fluorescence signal (left) in response to hypo-osmolar medium (150 mOsm) and return to iso-osmolarity (300 mOsm). The rate of water transport (right) in wildtype mice is three-fold higher than in AQP4 KO [reproduced from [160]]. (C) AQP4 (red) expression in GFAP (green) positive astrocytes of hippocampal dentate gyrus in a wildtype mouse. The colocalization of AQP4 and GFAP is revealed by yellow arrowheads. Scale bar, 40 µm. [reproduced from [52]]. (D) Structural diagram of the pore-forming subunit of Kir4.1 channel [reproduced from [69]]. (E) Representative whole-cell currents of wildtype astrocytes in CA1 stratum radiatum, which resulted from Kir4.1 channel activation [reproduced from [80]]. (F) Localization of Kir4.1 channels to astrocytic endfeet revealed by immunostaining in hippocampal tissue from a temporal lobe epilepsy patient. Red arrowhead, astrocyte soma; Red double arrowhead, astrocyte process; Red arrow, astrocyte endfeet. Scale Bar, 50 μm [modified from [84]].
Figure 3
Figure 3. Structure, function and localization of astrocytic voltage-gated Ca2+ channels and two-pore K+ channels
(A) Structural diagram of Cav channels. The α-interacting domain (AID; shown in red on the I–II linker) binds the Cavβ subunit with high affinity. The pore-forming loops between TM segments S5 and S6 are marked with ‘P’, and the voltage-sensor domain in TM segment S4 is indicated by ‘+’ signs [reproduced from [161]]. (B) Traces of Ca2+ activity measured by fluorescence of the Ca2+ indicator Fluo-4 along an astrocyte process imaged by two-photon microscopy of a brain slice [modified from [100]]. (C) Expression of Cav channels in reactive astrocytes near an amyloid-β plaque in a transgenic mouse model of Alzheimer’s disease, revealed by immunostaining and confocal microscopy. Green, Cav1.2 antibody; red, amyloid-β antibody. Scale bar, 20 µm [modified from [105]]. (D) Structural diagram of two-pore domain K+ channels [reproduced from [69]]. (E) Whole-cell current from a Xenopus laevis oocyte expressing TASK-3 channels [modified from [121]]. (F) Hippocampal astrocytes co-immunostained with TASK-2 (green) and GFAP (red). Nuclei are indicated by DAPI staining in blue [modified from [124]].
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Lang B, Vincent A. Autoantibodies to ion channels at the neuromuscular junction. Autoimmunity Reviews. 2003;2(2):94–100. - PubMed
    1. Vincent A. Developments in autoimmune channelopathies. Autoimmunity Reviews. 12(6):678–681. - PubMed
    1. van Coevorden-Hameete, et al. Molecular and cellular mechanisms underlying antineuronal antibody mediated disorders of the central nervous system. Autoimmunity Reviews. 2014;13:299–312. - PubMed
    1. Zlokovic BV. The blood-brain barrier in health and chronic neurodegenerative disorders. Neuron. 2008;57(2):178–201. - PubMed
    1. Quaegebeur A, Lange C, Carmeliet P. The neurovascular link in health and disease: molecular mechanisms and therapeutic implications. Neuron. 2011;71(3):406–424. - PubMed

Publication types