Regulation of neurovascular coupling in autoimmunity to water and ion channels

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 Ca2+ 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.

Activity‐dependent calcium, oxygen, and vascular responses in a mouse model of familial hemiplegic migraine type 1

“…[19][20][21][22][23] Voltage-gated Ca V calcium channels are absent or sparsely expressed in astrocytes, yet astrocytes are activated during increased neuronal activity and use calcium as a signaling molecule. [24][25][26] Therefore, we also investigated stimulation-evoked Ca 21 responses in astrocyte somas. Before CSD, whisker pad stimulation induced smaller calcium increases in the neuron and astrocyte somas of FHM1 mice compared to WT mice (p < 0.001 for both neuronal and astrocyte soma, linear mixed model of FHM1 vs WT; Fig 6A,B, left panels).…”

Signaling Pathways Regulating the Pathophysiological Responses of Astrocytes: A Focus on the IKK/NF-κB System

“…neurotransmitters (e.g. glutamate) and potassium ions released during synaptic activity [1,18,19]. Disruption of these astrocyte functions can cause edema formation and alters neuronal excitation and network activity, which can result in behavioral changes, epileptic seizures and excitotoxic neurodegeneration [3,18,19].…”

KIR4.1: K+ Channel Illusion or Reality in the Autoimmune Pathogenesis of Multiple Sclerosis

“…Different from MS, NMO is a primary astrocytopathy with secondary demyelination. MS and NMO also differ in pathological and imaging features, as well as in their responses to different immunotherapies (see recent reviews, Barnett and Sutton, 2012 ; Jukkola and Gu, 2015 ). In the CNS, AQP4 is predominantly localized to astrocytic endfeet contacting blood capillaries and synapses, similar to KIR4.1 (Figure 1B ).…”

“…Its binding proteins and other proteins involved in regulating astrocytic functions, such as KIR5.1 and AQP4, could also be the target causing similar disruption, and are worth of pursuing. Indeed, many ion channel proteins have been identified to express in resting or activated astrocytes (Jukkola and Gu, 2015 ). They include Kv channels, two-pore K + channels, several voltage-gated Ca 2+ and Na + channels, transient receptor potential channels, and gap junctions (Jukkola and Gu, 2015 ).…”

“…Indeed, many ion channel proteins have been identified to express in resting or activated astrocytes (Jukkola and Gu, 2015 ). They include Kv channels, two-pore K + channels, several voltage-gated Ca 2+ and Na + channels, transient receptor potential channels, and gap junctions (Jukkola and Gu, 2015 ). Their disruption also likely causes dysfunction of astrocytic signaling, leading to CNS malfunction.…”