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General Physiology of Glial Cells

5.1 Membrane potential and ion distribution

In general, mature macroglial cells have a negative resting membrane potential (— -80 to -90 mV), because of the predominance of potassium conductance, which maintains the membrane potential close to the potassium equilibrium potential (EK); however, astrocytes are heterogeneous with respect to membrane potentials and potassium conductances, and the 'text-book' view of astrocytes as a homogeneous population of cells with a highly negative membrane potential close to the EK is an oversimplification (see below). Electrical depolarization of glia results in electrotonic changes of the membrane potential and does not produce regenerative action potentials. The ion distribution across glial membranes is similar to other cells (intracellular K+ concentration is -100-140 mM; Na+ < 10 mM, Ca2+ < 0.0001 mM). The main exception is Cl-, which is unusually high in both astrocytes and oligodendrocytes ([Cl-] - 30-40 mM), due to the high activity of Na+/K+/2Cl- cotransporters, which transport 2Cl- into the cell in exchange for 1 K+ and 1 Na+.

5.2 Ion channels

Glial cells express all major types of voltage-gated ion channels, including K+, Na+ and Ca2+, and various types of anion channels (Table 5.1). Biophysically these channels are similar to those found in other types of cells such as nerve or muscle cells.

Potassium voltage-gated channels are most abundantly present in various types of neuroglia. These channels are represented by four families, known as the inward rectifier K+ channels (Kir), delayed rectifier potassium channels (KD), rapidly inactivating A-type channels (KA) and calcium-activated K+ channels (KCa).

Inward rectifier potassium channels are present in practically all mature neuroglial cells and are responsible for their very negative (-80 to -90 mV) resting

Table 5.1 Ion channels in glial cells

Ion channel

Molecular identity

Localization

Main function

Calcium channels

Cay

Immature astrocytes and

Generation of

oligodendrocytes

Ca2+ signals

Sodium channels

Nay

Astroglial precursors;

Regulation of

cells of glia-derived

proliferation (?)

tumours

Delayed rectifier

Kd, Ka Kca

Ubiquitous

Maintenance of

potassium channels

Kv 1.4, 1.5

resting membrane

Ca2+-dependent K+

TREK/TASK

potential; glial

channels

proliferation and

2-Pore-domain K+

reactivity

channels

Inward rectifier

Kjj.4.1 (predominant)

Ubiquitous

Maintenance of

potassium channels

Kir 2.1, 2.2, 2.3

resting membrane

Kr 3.1

potential

K 6.1, 6.2

K+ buffering

Chloride channels

?

Ubiquitous

Chloride transport;

regulation of cell

volume

Aquaporins (water

AQP4 (predominant)

AQP4 - ubiquitous

Water transport

channels)

AQP9

AQP9 - astrocytes in

brain stem; ependymal

cells; tanycytes in

hypothalamus and in

subfornical organ

membrane potential. They are called inwardly (or anomalously) rectifying because of their peculiar voltage-dependence: these channels tend to be closed when the membrane is depolarized and are activated when the membrane is hyperpolarized to the levels around or more negative than the EK. In other words, these channels favour potassium diffusion in the inward direction over the outward one. These channels set the resting membrane potential; the Kir channels are regulated by extracellular K+ concentration, and increases in the latter result in inward flow of K+ ions, which is important for K+ removal from the extracellular space, considered a primary physiological function of astrocytes (see Chapter 7).

Molecularly, there are more than 20 types of inwardly rectifying K+ channels (or Kjr channels), and glia express representatives of most kinds. Glia (astrocytes, oligodendrocytes, Müller glia and Bergmann glia) are characterized by expression of the Kjj.4.1 subtype, which is almost exclusively glial in the CNS, and a critical role for Kjj.4.1 in setting the negative glial membrane potential has been demonstrated in Kjr4.1 knockout mice. In addition to Kir4.1, glia express diverse Kir, including: Kir5.1, which do not form functional homomeric channels, but form heteromeric channels by a specific coassembly with Kjr4.1; members of the strongly rectifying and constitutively active K 2.0 family (e.g. Kjr2.1, 2.2 and 2.3), which may also specifically coassemble with Kir4.1 in glia; Kjr3.0 channels (e.g. Kir3.1), which are coupled to a range of G-protein linked neurotransmitter receptors (Kir3.0 channels are generally formed by coassembly of Kir3.1 subunits with other members of the same family, such as the Kir3.1/Kir3.4 heteromers in atrial myocytes, which are responsible for the acetylcholine (ACh)-induced deceleration of heart beat); and ATP-dependent Kir (Kir6.1 and 6.2), which are only active when intracellular concentrations of ATP fall to very low levels and therefore serve to maintain the high K+ conductance and hyperpolarized resting membrane potential in glia during metabolic challenge. Glia also express two-pore domain K+ (2PK) channels, which are responsible for the background or leak K+ conductance and are involved in setting the resting membrane potential and ion and water homeostasis; glia express TREK and TASK subtypes of 2PK channels.

Delayed rectifier potassium channels, rapidly inactivating A-type channels, and calcium-dependent channels are expressed in practically every type of glial cell. Molecularly, glial cells express multiple KD channel subtypes, but apparently only one KA channel subtype, Kv1.4, which may form heteromers with the KD channel subunit Kv 1.5. Three types of KCa can be distinguished by their biophysical properties (BK, IK and SK), and glia express both BK and SK; BK channels are strongly voltage-dependent and sensitive to micromolar calcium, whereas SK are weakly voltage-dependent and sensitive to nanomolar calcium. KD, KA and KCa are all closed at the resting membrane potential and their activation requires depolarization of the cell membrane to values more positive than -40 mV. Hence, the functional role of these channels in glial cells remains unclear. However, they may be activated when extracellular potassium concentration is elevated sufficiently to depolarize the cell membrane; for example, Kv1.5 and BK channels are localized to Schwann cell membranes at nodes of Ranvier, where localized increases in K+ and Ca2+ during action potential propagation may be sufficient for them to open, and the consequent K+ efflux may play a role in the post-stimulus recovery of extracellular potassium levels. Although the function of KD in mature glia is unclear, they are important for glial proliferation during development and following CNS injury.

Voltage-gated sodium channels (NaV) are found in many types of astroglial cells, including retinal astrocytes, astrocytes from hippocampus, cortex and spinal cord, and in Schwann cells. The molecular structure and biophysical properties of NaV channels expressed in glial cells are similar to those present in neurones or muscle cells. The main difference is the channel density: glial cells have about one NaV channel per 10 ^m2, whereas their density in neurones can reach 100010 000 per 1 ^m2. The role of NaV channels in glia remains unclear; interestingly glial progenitor cells may have a much higher density of NaV, similarly very high densities of NaV were found in tumours of glial origin, and it may be that

NaV channels are somehow involved in the control of glial cell proliferation, differentiation or migration.

Voltage-gated calcium channels (CaV) are usually detected in glial precursors or in immature glial cells, and may be important for generating local elevations in cytosolic calcium concentration relevant for controlling growth or migration of neuroglial precursors. Current evidence is that CaV are down-regulated during glial development, but they are up-regulated in reactive astrocytes, consistent with a role for CaV in proliferation and growth. The localization of CaV to the processes of immature oligodendrocytes suggests a role in myelination. Müller glia express mRNA for CaV subunits, and astrocytes and myelinating oligodendrocytes may express voltage-gated calcium channels in microdomains. The expression of CaV by mature glia remains uncertain, because of the inability of patch-clamp and calcium-imaging techniques to identify small currents or calcium signals that may occur at distal processes.

Chloride and other anion channels several types have been demonstrated in astrocytes, oligodendrocytes and Schwann cells. Importantly, astrocytes are able to actively accumulate Cl-, resulting in a relatively high intracellular Cl- concentration (about 35 mM), largely through the activity of Na+/K+/Cl- cotransporters. The equilibrium potential for Cl- in astrocytes lies around -40 mV, and therefore opening of Cl- -selective channels leads to Cl- efflux (manifested electrically as an inward current depolarizing the cells, because of loss of anions). The Cl- channels may be involved in astrocyte swelling and in the regulation of extracellular Cl- concentration.

Aquaporins are integral membrane proteins, which form channels permeable to water and to some other molecules e.g. glycerol and urea. There are at least 10 different types of aquaporins (AQP1 to AQP10) in mammalian cells, and AQP4 is expressed almost exclusively by astrocytes throughout the brain; in addition astrocytes also have small amounts of AQP9. Aquaporins are concentrated on astroglial perivascular endfeet, where they are colocalized with Kir4.1; they may be particularly important during cerebral oedema, when astroglial perivascular endfeet swell considerably and protect the surrounding neurones. In the hypothalamus and in osmosensory areas of the subfornical organ, tanycytes exclusively express AQP9 (and they do not possess AQP4), which may be involved in regulation of systemic water homeostasis.

5.3 Receptors to neurotransmitters and neuromodulators

Glial cells are capable of expressing the same extended variety of receptors as neurones do, which allows glia to actively sense information delivered by neuro-

transmitters released during synaptic transmission. Glia, similar to neurones, are endowed with both ionotropic and metabotropic receptors, and the main classes of glial neurotransmitter receptors are summarized in Table 5.2.

Initial experiments on astroglial cells isolated from the brain and grown in culture demonstrated that these cells are capable of expressing almost all types of neurotransmitter receptor (Figure 5.1), and moreover different cells may have quite

Astrocyte Oligodendrocyte

Astrocyte Oligodendrocyte

Schwann Cell Drg Culture

Figure 5.1 Neurotransmitter receptors in glial cells - scheme showing the multiplicity of neurotransmitter receptors expressed in different types of glial cells. IICR - InsP3-induced Ca2+release; CICR - Ca2+-induced Ca2+ release.

Ionotropic receptors: NChr - Nicotinic Cholinoreceptors; GABAaR - GABA receptors; GLY - glycine receptors; GluR - glutamate receptors (AMPA, NMDA and KA receptors); P2X - purinoreceptors.

Metabotropic receptors: VIP - vasoactive intestinal polypeptide receptors; MChR -muscarinic cholinoreceptors; NPY - neuropeptide Y receptors; mGluR - metabotropic glutamate receptors; BK - bradykinin receptors; V2 - vasopressin receptors; HjR - histamine receptors; OX - oxytocin receptors; P2Y - metabotropic purinoreceptors; ajAR - adrenergic receptors; SbP - substance P receptors; PAF - platelet activating factor receptors; ETB - endothelin receptors; 5-HT - serotonin receptors

Figure 5.1 Neurotransmitter receptors in glial cells - scheme showing the multiplicity of neurotransmitter receptors expressed in different types of glial cells. IICR - InsP3-induced Ca2+release; CICR - Ca2+-induced Ca2+ release.

Ionotropic receptors: NChr - Nicotinic Cholinoreceptors; GABAaR - GABA receptors; GLY - glycine receptors; GluR - glutamate receptors (AMPA, NMDA and KA receptors); P2X - purinoreceptors.

Metabotropic receptors: VIP - vasoactive intestinal polypeptide receptors; MChR -muscarinic cholinoreceptors; NPY - neuropeptide Y receptors; mGluR - metabotropic glutamate receptors; BK - bradykinin receptors; V2 - vasopressin receptors; HjR - histamine receptors; OX - oxytocin receptors; P2Y - metabotropic purinoreceptors; ajAR - adrenergic receptors; SbP - substance P receptors; PAF - platelet activating factor receptors; ETB - endothelin receptors; 5-HT - serotonin receptors

Table 5.2 Neurotransmitter receptors in glial cells

Receptor type

Properties/ physiological effect

Localization in situ

Astrocytes Ionotropic receptors A. Glutamate receptors AMPA/Kainate

NMDA receptors

B. GABAAreceptors

C. P2X (ATP) Purinoreceptors

D. Glycine receptors

E. Nicotinic cholinoreceptors NChR

Metabotropic receptors A. Glutamate receptors (mGluRs)

Na+/K+ channels

Na+/K+/Ca2+ channels

Activation triggers cationic current and cell depolarization

Na+/K+/Ca2+ channels Activation triggers inward Ca2+/Na+ current, cell depolarization and substantial Ca2+ entry CI- channel

Activation triggers CI- efflux and cell depolarization

Na+/K+/Ca2+ channels

Activation triggers cationic current, cell depolarization and may also cause Ca2+ entry

Cl~ channel

Activation triggers CI- efflux and cell depolarization

Na+/K+/Ca2+ channels

Group I (mGluRl,5) control PLC, InsP3 production and Ca2+ release from the ER Group II (mGluR2,3) and Group III (mGluR4,6,7) control synthesis of cAMP

Ubiquitous (grey matter in hippocampus, cortex, cerebellum, white matter)

Bergmann glial cells, immature astrocytes

Cortex, spinal cord

Ubiquitous (hippocampus, cortex, cerebellum, optic nerve, spinal cord, pituitary gland)

P2X receptor molecules expressed in cortex, cerebellum, optic nerve; functional activation shown in retina

Currents mediated by P2X7 receptors are found in retinal Müller cells

Spinal cord

Cerebellum

Ubiquitous

B. GABAg receptors

C. Adenosine receptors

D. P2Y (ATP) Purinoreceptors

E. Adrenergic receptors axAR, a2AR

JSjAR, &AR

F. Muscarinic cholinoreceptors mChR M,-M5

G. Oxytocin and vasopressin receptors

H. Vasoactive Intestinal Polypeptide receptors (VIPR 1,2,3)

I. Serotonin receptors 5 HT1a, 5-HT2A, 5-HTsa J. Angiotentsin receptors AT,, AT2

K. Bradykinin receptors

Control PLC, InsP3 production and Ca2+ release from the ER Ax receptors control PLC, InsP3 production and Ca2+ release from the ER A2 receptor increase cAMP

Control PLC, InsP3 production and Ca2+ release from the ER

Control PLC, InsP3 production and Ca2+ release from the ER Control glial cell proliferation and astrogliosis; /32AR are up-regulated in pathology

Control PLC, InsP3 production and Ca2+ release from the ER

Control PLC, InsP3 production and Ca2+ release from the ER; may regulate water channel (aquaporin)

Control PLC, InsP3 production and Ca2+ release from the ER; may regulate energy metabolism, expression of glutamate transporters, induce release of cytokines and promote proliferation

Increase in cAMP, energy metabolism

Control PLC, InsP3 production and Ca2+ release from the ER

Control PLC, InsP3 production and Ca2+ release from the ER

Hippocampus Hippocampus, cortex

Ubiquitous

Hippocampus, Bergmann glial cells Cortex, optic nerve

Hippocampus, amygdala Hypothalamus, other brain regions(?)

Supraoptic nucleus; other brain regions(?)

White matter (optic nerve, corpus callosum, white mater tracts in cerebellum and subcortical areas) ?

Table 5.2 (Continued)

Receptor type

Properties/ physiological effect

Localization in situ

L. Thyrotropic-releasing hormone receptors, TRH, M. Opioid receptors, (jl, 8, k

N. Histamine receptors,

Hx h2

O. Dopamine receptors

Di d2

Oligodendrocytes Ionotropic receptors A. Glutamate receptors AMPA/Kainate

NMDA

B. GABAa receptors

Inhibition of DNA synthesis, proliferation and growth, inhibition of cAMP production

Control PLC, InsP3 production and Ca2+ release from the ER Control synthesis of cAMP

Control synthesis of cAMP Trigger Ca2+ signals

Activation triggers cationic current and cell depolarization

Ca2+/Na+/K+channels

Cl~ channel

Activation triggers CI- efflux and cell depolarization

Spinal cord Hippocampus

Hippocampus, cerebellum

Cortex

Corpus callosum, spinal cord, optic nerve

Optic nerve, corpus callosum, cerebellar white matter; may be activated upon pathological insult and contribute to oligodendrocyte death Corpus callosum

C. Glycine receptors

Metabotropic receptors

A. Muscarinic cholinoreceptors mChR Mx, M2

B. P2Y (ATP) Purinoreceptors Microglia

Ionotropic receptors

A. P2X (ATP) Purinoreceptors

B. Glutamate receptors AMPA/Kainate

Metabotropic receptors

A. P2Y (ATP) Purinoreceptors

B. GABAb receptors

C. Muscarinic cholinergic receptors

D. Cytokine/complement receptors

Cl- channel

Activation triggers Cl- efflux and cell depolarization

Control synthesis of cAMP

Control PLC, InsP3 production and Ca2+ release from the ER

Na+/K+/Ca2+ channels Activation triggers cationic current and cell depolarization; may also cause substantial Ca2+ influx Na+/K+ channels

Activation triggers cationic current and cell depolarization

Control PLC, InsP3 production and Ca2+ release from the ER Modulate interleukin release Control PLC, InsP3 production and Ca2+ release from the ER

Control PLC, InsP3 production and Ca2+ release from the ER, control energy status, regulate release of pro-inflammatory factors

Spinal cord

Corpus callosum

Ubiquitous; specifically important are P2X7 receptors, which trigger release of cytokines. Expression of P2X receptors is modulated by microglial activation ?

Ubiquitous

Cultures rat and human microglia Ubiquitous

Table 5.2 (Continued)

Receptor type

Properties/ physiological effect

Localization in situ

E. Chemokine receptors (CCR1-5,

Control PLC, InsP3 production and Ca2+

Ubiquitous

CXCR4 etc.)

release from the ER; may activate JAK/STAT

and NF-kB pathways

F. Endothelin receptors, ETB

Control PLC, InsP3 production and Ca2+

Ubiquitous

release from the ER

Schwann cells

Ionotropic receptors

A. P2X (ATP) Purinoreceptors

Na+/K+/Ca2+ channels

Ubiquitous; P2X7 receptors are particularly

Activation triggers cationic current and cell

strongly expressed

depolarization; may also cause substantial

Ca2+ influx

Metabotropic receptors

A. P2X (ATP) Purinoreceptors

Control PLC, InsP3 production and Ca2+

Ubiquitous

release from the ER

B. Endothelin receptors, ETB

Promote Schwann cells proliferation; may be

?

involved in pain mechanisms

C. Tachykinin receptors, NKX

Control PLC, InsP3 production and Ca2+

?

release from the ER

different complements of these receptors. When expression of neurotransmitter receptors was further investigated in in situ preparations in brain slices, it turned out that astrocytes in different brain regions express a very distinct and limited set of receptors, specific for neurotransmitters released in their vicinity. For example (Figure 5.2) Bergmann glial cells express receptors that exactly match the modality of receptors expressed by its neuronal neighbour, Purkinje neurone. In both cells, the repertoire of receptors is optimized to sense neurotransmitters released by neuronal afferents, which form synapses on this neurone-glial unit. Receptor expression can be even more spatially segregated: the same Bergmann glial cells specifically concentrate receptors for GABA in the membranes surrounding inhibitory synapses signalling to Purkinje neurones. Therefore, the expression of specific receptors is selectively regulated, which makes astrocytes perceptive towards chemical signals specific for each particular region of the brain. As shown

Glial Cells And Their Functions
Figure 5.2 Receptors expressed in Bergman glial cell in situ are limited to those specific to neurotransmitters released in their vicinity. (Used with permission from Verkhratsky et al., 'Glial calcium: homeostasis and signaling function', Physiological Reviews, 78, 99-141 © 1998)

in Table 5.2, astroglial cells may express a wide variety of receptors; the main types are glutamate receptors, purinoreceptors and GABA receptors. In addition, astrocytes express multiple receptors to neuropeptides, cytokines and chemokines, which are particularly important for regulation of growth and differentiation and for pathological reactions of glial cells.

Oligodendrocytes, in general, express fewer types of neurotransmitter receptors compared to astroglial cells (Table 5.2). Among the most abundant receptors in oligodendrocytes are metabotropic P2Y purinoreceptors, which control cytosolic Ca2+ signalling. Immature oligodendrocytes and OPCs also express adenosine (A1) receptors. Oligodendrocytes appear to express ionotropic glutamate receptors of the AMPA/KA kind at all stages of their development, and recent data indicates they also express NMDA receptors. OPCs and immature oligodendrocytes can also express GABAA receptors, which induce cell depolarization, similar to astrocytes. OPCs also express metabotropic glutamate and GABA (GABAb) receptors, which regulate OPC differentiation in vitro. In the spinal cord, where glycine acts as an important neurotransmitter, immature oligodendrocytes express glycine receptors. Receptors for adenosine, glutamate, GABA and glycine are highly developmentally regulated, and are likely to play an important role in the neuronal regulation of oligodendrocyte differentiation and myelination. Similar functions in oligodendrocyte development have been suggested for cholinoreceptors (both muscarinic and nicotinic ACh receptors). Mature myelinating oligodendrocytes express AMPA- and NMDA-type glutamate receptors and P2Y purinoreceptors (and probably P2X (e.g. P2X7) purinorecep-tors). NG2-glia express functional AMPA-type glutamate receptors and GABAA receptors.

Microglia express a surprizingly large variety of neurotransmitter receptors, including glutamate, GABA and cholinoreceptors. Microglial cells abundantly express purinoreceptors of both the ionotropic and metabotropic variety. Particularly important for microglial function are receptors of the P2X7 subtype, which are activated by high extracellular ATP concentrations; activation of P2X7 receptors results in the appearance of a large transmembrane pore, which allows massive influx of cations and may even permit the release of biologically active substances from microglial cells. It is believed that P2X7 receptors may act as sensors for neuronal damage, as the latter is accompanied by a substantial release of ATP. In addition, microglial cells express receptors for various cytokines and chemokines, numerous inflammatory factors, such as complement and complement fragments, and other biologically active molecules including endothelin, thrombin, platelet activating factor, etc.

Finally, Schwann cells express purinoreceptors of both ionotropic (P2X) and metabotropic (P2Y) varieties, which can be excited by ATP released during nerve activity; activation of purinoreceptors triggers intracellular Ca2+ signalling events. In addition, Schwann cells are sometimes endowed with endothelin (ETA and ETB) receptors and tachykinin receptors of the NK1 type. The ETA receptors in Schwann cells may be involved in transmission of chronic inflammatory pain.

Below, we shall overview the main types of neurotransmitter receptors expressed in glial cells.

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