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Review
. 2023 Oct 11;13(10):2038.
doi: 10.3390/life13102038.

Ion Channels and Ionotropic Receptors in Astrocytes: Physiological Functions and Alterations in Alzheimer's Disease and Glioblastoma

Annamaria Lia  1 , Alessandro Di Spiezio  1   2 , Lorenzo Vitalini  3 , Manuela Tore  4   5 , Giulia Puja  3 , Gabriele Losi  4   5
Affiliations
Review

Ion Channels and Ionotropic Receptors in Astrocytes: Physiological Functions and Alterations in Alzheimer's Disease and Glioblastoma

Annamaria Lia et al. Life (Basel). .

Abstract

The human brain is composed of nearly one hundred billion neurons and an equal number of glial cells, including macroglia, i.e., astrocytes and oligodendrocytes, and microglia, the resident immune cells of the brain. In the last few decades, compelling evidence has revealed that glial cells are far more active and complex than previously thought. In particular, astrocytes, the most abundant glial cell population, not only take part in brain development, metabolism, and defense against pathogens and insults, but they also affect sensory, motor, and cognitive functions by constantly modulating synaptic activity. Not surprisingly, astrocytes are actively involved in neurodegenerative diseases (NDs) and other neurological disorders like brain tumors, in which they rapidly become reactive and mediate neuroinflammation. Reactive astrocytes acquire or lose specific functions that differently modulate disease progression and symptoms, including cognitive impairments. Astrocytes express several types of ion channels, including K+, Na+, and Ca2+ channels, transient receptor potential channels (TRP), aquaporins, mechanoreceptors, and anion channels, whose properties and functions are only partially understood, particularly in small processes that contact synapses. In addition, astrocytes express ionotropic receptors for several neurotransmitters. Here, we provide an extensive and up-to-date review of the roles of ion channels and ionotropic receptors in astrocyte physiology and pathology. As examples of two different brain pathologies, we focus on Alzheimer's disease (AD), one of the most diffuse neurodegenerative disorders, and glioblastoma (GBM), the most common brain tumor. Understanding how ion channels and ionotropic receptors in astrocytes participate in NDs and tumors is necessary for developing new therapeutic tools for these increasingly common neurological conditions.

Keywords: Alzheimer’s disease; astrocytes; glia; glioblastoma; ion channels.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Ion permeable channels and receptors in astrocytes. Schematic view of the main ion channels and ionotropic receptors in astrocyte processes in a tripartite synapse. Ion channels (top), from left to right: tension gated PIEZO-1 channel; endoplasmic reticulum (ER)-STIM1 activated ORAI channels (ORAI-1,-3); TRP channels (TRPV4 is depicted, and others include TRPA1, TRPV1, TRPC1, and TRPC4-6); potassium permeable channels Kir (Kir 4.1, Kir 5.1, and KATP, which include Kir 2.1-3 and Kir 6.1-2), Kv (Kv1.1, Kv1.6, Kv3.4, and Kv4.3), K2P (TREK1-2 and TWIK1), and KCa (KCa1.1, KCa3.1, and KCa2.1-3, also known as BK, IK, and SK, respectively); sodium channels (Nav1.2-3 and Nav1.5-6); and anion permeable channels (CLC1-3, VRAC, MAC, and Best-1). The Na+Ca2+ exchanger (NCX) is also reported. Ionotropic receptors and others (bottom), from left to right: hemichannels composed of Cx 43, 30, and 26; purinegic P2X receptors (P2X7); GABAA receptors; cholinergic nicotinic receptors (nACh); and glutamatergic ionotropic receptors (NMDA, AMPA, and KA). Metabotropic receptors coupled to G protein (GPCRs) and electrogenic glutamate and GABA transporters (Glt and GAT1-3, respectively) are also reported. NT, neurotransmitter; Glut, glutamate. Obtained from Biorender.
Figure 2
Figure 2
Ion permeable channels and receptors in astrocytes in AD and GBM. (A) Schematic view of an Aβ plaque surrounded by reactive astrocytes (green) and microglia (yellow), together with Aβ fibrils and neurons (purple). Ion channels and ionotropic receptors reported in Table 1 are highlighted below with information about their expression changes and the consequent protective or detrimental effects on brain functions. (B) Schematic view of GBM cells surrounded by reactive astrocytes (green) and microglia (yellow), together with neurons (purple). The different colors of the GBM cells highlight the GBM cell heterogeneity. Ion channels and ionotropic receptors reported in Table 2 are highlighted below with information about expression changes in GBM cells and their effects in promoting tumor proliferation, migration, or resistance to chemotherapy. Synaptic contacts between neurons are omitted for simplicity. Obtained from Biorender.
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Grants and funding

This research was funded by Italian Ministry of University and Research (MUR), grant PRIN2020 n.2020AMLXHH to G.L.
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