Glial syncytium gap junctions

Macroglial cells in the brain are physically connected, forming a functional cellular syncytium. This represents a fundamental difference between neuronal and glial networking. For the vast majority of neurones, networking is provided by synaptic contacts. The latter preclude physical continuity of the neuronal network, while providing for functional inter-neuronal signal propagation. In contrast, glial networks are supported by direct intercellular contacts, generally known as gap junctions.

The gap junctions are, in fact, present in many types of mammalian cells, where they are responsible for metabolic (e.g. in liver) and electrical (e.g. in the heart) coupling. At the ultrastructural level (seen by electron microscopy, EM, and freeze fracture EM), gap junctions appear as specialized areas where two apposing membranes of adjacent cells come very close together, so that the intercellular cleft is reduced to a width of about 2-2.5 nm. Within these areas, each gap junction is made up of many hundreds of intercellular channels comprised of specialized proteins known as connexons; these form an intercellular channel which is in essence a large aqueous pore connecting the cytoplasm of both adjacent cells (Figure 5.7). Each intercellular channel is thus composed of two precisely aligned connexons (also known as hemichannels), one in each of the cell membranes of the two adjacent coupled cells.

On a molecular level, each connexon is composed of six symmetrical subunits, named connexins; hence, a functional intercellular channel comprises two connexons made up of twelve connexins. The connexins are many, and about 20 subtypes have been identified in mammalian tissues. These subtypes differ in

Structure Schwann Cell

Figure 5.7 Structure of gap junctions - these are intercellular channels between two closely apposed cellular membranes, with the gap between cells ~2-3 nm wide. The intercellular channels are formed by two apposed hemichannels or connexons. Each connexon, in turn, is composed from six subunits known as connexins (see the text for further explanation). The gap junction channels permit intercellular movement of solutes with a m.w. up to 1000 Da, such as ions, second messengers and metabolites

Figure 5.7 Structure of gap junctions - these are intercellular channels between two closely apposed cellular membranes, with the gap between cells ~2-3 nm wide. The intercellular channels are formed by two apposed hemichannels or connexons. Each connexon, in turn, is composed from six subunits known as connexins (see the text for further explanation). The gap junction channels permit intercellular movement of solutes with a m.w. up to 1000 Da, such as ions, second messengers and metabolites molecular weight (which varies between 26 kDa and 62 kDa), which is used in connexin nomenclature, e.g. Cx43 and Cx32 are the most abundant connexins in astrocytes and oligodendrocytes, respectively. Each connexin has four transmembrane domains, which form the channel pore and gating mechanism.

The connexons may be formed from identical connexins (and then they are called homomeric), or several different connexins (heteromeric). Similarly, connexons in adjacent cells can be identical (making a homotypic gap junctional channel) or different (and then the channel is called heterotypic).

To produce a functional gap junction, several tens to hundreds of connexons must form a cluster; these clusters may connect similar cells (e.g. astrocyte to astrocyte) making a homocellular gap junction, or different cells (e.g. astrocyte and oligodendrocyte) forming a heterocellular gap junction. The connexons positioned away from the clusters do not form transcellular channels; instead they remain in to form the hemichannels, which may be activated under certain conditions.

The intercellular channels formed by connexons are large pores with diameter ~1.5 nm, which are permeable to relatively large molecules with molecular weight up to 1 kDa. This is a very important feature, as it allows intercellular diffusion of many cytoplasmic second messengers (e.g. InsP3), nucleotides (ATP, ADP), and even vitamins. Obviously, these large pores are permeable to ions, and therefore they also provide for effective electrical coupling. The biophysical behaviour of intercellular channels is very similar to any other type of membrane ion channel as they undergo rapid transition between 'open' and 'closed' states. Importantly, the permeability and opening of gap junctional channels are controlled by many intracellular factors. For example, large increases in cytoplasmic Ca2+ (>10 ^M) and intracellular acidification effectively inhibit junctional conductance. The junc-tional permeability may also be controlled by intracellular second messengers such as cAMP, or by intracellular kinases such as PKC. The pharmacology of gap junctions is poorly defined, yet they can be effectively blocked by volatile anaesthetics (halothane) and several alcohols (octanol or heptanol).

Astroglial cells in the CNS have the highest density of gap junctions (on a molecular level, astrocytes predominantly express Cx43, Cx30 and Cx26) and hence the highest degree of intercellular coupling. On average, a pair of astrocytes in the grey matter is connected by ~230 gap junctions. Indeed, injection of relatively small fluorescent molecules (e.g. Lucifer yellow, m.w. ~450-500 Da, or Alexa dyes with m.w. ~450 Da) into a single astrocyte in brain tissue results in staining of about 50-100 neighbouring astroglial cells. Yet the networks formed by gap junctions are not absolutely ubiquitous and the degree of coupling varies considerably between different brain regions. For example, almost all cortical astrocytes are integrated into the syncytium, whereas in the optic nerve the degree of coupling reaches ~80 per cent and in hippocampus it is much lower, being around ~50 per cent.

Oligodendrocytes also express several subtypes of connexins (Cx29, Cx32, Cx45, Cx47) and form both homocellular gap junctions with adjacent oligoden-drocytes and heterocellular gap junctions with astroglial cells. Coupling between oligodendrocytes is much weaker compared to astrocytes, and usually every oligodendrocyte is coupled with two to four of its neighbours. The degree of this coupling is very different between various brain regions and also between species. Very often oligodendrocytes form gap junctions with astrocytes, the latter providing a general integrating media, which forms a 'panglial syncytium' within the brain. This integration also extends to ependymal cells, as the latter form gap junctions with astrocytes and also with other ependymocytes (Figure 5.8). Astrocytes may occasionally form gap junctional contacts with neurones, especially at early developmental stages.

Resting microglia do not contact each other and are not coupled to each other or to other glia (although activated microglia can express Cx43 in vitro). Similarly, NG2-glia are not functionally coupled to each other or to other glia; it is not known

Schwann Cells

Figure 5.8 Gap junctions are instrumental in forming a panglial syncytium in the CNS. Astrocytes are considered to form a glial syncytium via extensive gap junctional communication. The scheme shows astrocytes forming gap junction contacts with each other and with oligodendrocytes, ependymal cells, and maybe even with some neurones. In addition, astrocytes receive chemical signals from synapses, and completely ensheath blood vessels with their perivascular endfeet. In this way, astrocytes integrate the brain into a functional syncytium

Figure 5.8 Gap junctions are instrumental in forming a panglial syncytium in the CNS. Astrocytes are considered to form a glial syncytium via extensive gap junctional communication. The scheme shows astrocytes forming gap junction contacts with each other and with oligodendrocytes, ependymal cells, and maybe even with some neurones. In addition, astrocytes receive chemical signals from synapses, and completely ensheath blood vessels with their perivascular endfeet. In this way, astrocytes integrate the brain into a functional syncytium whether they express connexins. The lack of coupling in microglia and NG2-glia enables them to act individually in isolation from the glial syncytium, which may be particularly important at sites of brain injury.

Schwann cells express Cx32 and Cx46. Immature Schwann cells express Cx46 during development and following injury and are coupled to one another, whereas myelinating Schwann cells express Cx32, which connect paranodal loops of the myelin sheaths, where they are involved in ion and water movement.

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