General Physiology of Glial Cells
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 theinward rectifier K+ channels (Kir), delayed rectifier potassium channels (KD), rapidly inactivating A-type channels(KA) andcalcium-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
Glial Neurobiology: A Textbook Alexei Verkhratsky and Arthur Butt
© 2007 John Wiley & Sons, Ltd ISBN 978-0-470-01564-3 (HB); 978-0-470-51740-6 (PB)
40 CH05 GENERAL PHYSIOLOGY OF GLIAL CELLS Table 5.1 Ion channels in glial cells
Ion channel Molecular identity Localization Main function
Calcium channels CaV Immature astrocytes and
oligodendrocytes
Generation of Ca2+signals
Sodium channels NaV Astroglial precursors;
cells of glia-derived tumours
Regulation of proliferation (?) Delayed rectifier
potassium channels Ca2+-dependent K+
channels
2-Pore-domain K+ channels
KD, KAKCa Kv1.4, 1.5 TREK/TASK
Ubiquitous Maintenance of
resting membrane potential; glial proliferation and reactivity Inward rectifier
potassium channels
Kir4.1 (predominant) Kir 2.1, 2.2, 2.3 Kir 3.1 Kir 6.1, 6.2
Ubiquitous Maintenance of
resting membrane potential
K+buffering
Chloride channels ? Ubiquitous Chloride transport;
regulation of cell volume
Aquaporins (water channels)
AQP4 (predominant) AQP9
AQP4 – ubiquitous AQP9 – astrocytes in brain stem; ependymal cells; tanycytes in hypothalamus and in subfornical organ
Water transport
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 Kir channels), and glia express representatives of most kinds. Glia (astrocytes, oligodendrocytes, Müller glia and Bergmann glia) are characterized by expres- sion of the Kir4.1 subtype, which is almost exclusively glial in the CNS, and a critical role for Kir4.1 in setting the negative glial membrane potential has been demonstrated in Kir4.1 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 Kir4.1; members of the
5.2 ION CHANNELS 41 strongly rectifying and constitutively active Kir 2.0 family (e.g. Kir2.1, 2.2 and 2.3), which may also specifically coassemble with Kir4.1 in glia; Kir3.0 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 Kv1.5. Three types of KCacan 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 KDin 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 10m2, whereas their density in neurones can reach 1000–
10 000 per 1m2. 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
42 CH05 GENERAL PHYSIOLOGY OF GLIAL CELLS
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 CaVin proliferation and growth. The localization of CaVto 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−concen- tration (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−chan- nels 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.