The broad class of purinoreceptors are represented by molecules sensing various purinergic nucleotides, which are commonly present in the brain interstitium. These purinergic nucleotides, represented by adenosine triphosphate, adenosine and their metabolites, are released from both neurones and glial cells in several ways. Generally, purinoreceptors are divided into adenosine (A) receptors and ATP or P2 receptors of the P2X (ionotropic) and P2Y (metabotropic) subtypes (Figure 5.4). All glial cell types have been shown to express adenosine, P2X and P2Y receptors.
All three types of adenosine receptors (of A1-A3 types) are expressed in astroglial cells, although their exact role in astrocytes from different brain regions remains mostly unknown; astrocytes release ATP, which is the primary astroglial signalling molecule ('gliotransmitter'), and ATP is rapidly broken down to adenosine, which may serve as a 'gliotransmitter' in some areas. The adenosine receptors are coupled with G-proteins and exert several metabotropic effects. For example, A1 and A3 receptors inhibit glial proliferation, whereas A2 receptors have a stimulatory effect. In addition, stimulation of adenosine receptors may regulate expression of glutamate transporters, sensitivity of cells to glutamate, etc. Adenosine receptors are expressed by OPCs and immature oligodendrocytes, and they mediate axon-glial signalling during myelination. Myelinating and nonmyelinating Schwann cells express adenosine receptors, but they are not involved in axon-glial signalling.
The P2 ATP-receptors (Figure 5.4) are abundantly expressed in all types of glial cells. The expression is particularly prominent for metabotropic P2Y receptors, which are present almost in all types of astrocytes, oligodendrocytes, and microglia throughout the brain and spinal cord, as well as in Schwann cells. These receptors are represented by an extended family (P2Y1 to P2Y14); functionally they are
Figure 5.4 P2 (ATP) purinoreceptors are divided into ionotropic (P2X) and metabotropic (P2Y) receptors.
P2X receptors are ligand-gated cation channels, which upon ATP binding undergo rapid conformational change that allows the passage of Na+, K+ and Ca2+ through the channel pore (Ca2+ permeability relative to monovalent cations can range between 2 and 12 depending on the subunit composition). P2X receptors are formed from seven subunits, P2X1 to P2X7, encoded by distinct genes. The P2X1-6 subunits may form homo- or heteromeric receptors, with each functional receptor containing at least three monomers. On activation, P2X7 receptors can form a large pore, which allows passage of molecules with m.w. up to 900-1000 Da; it is generally considered that P2X7 receptors are activated by high concentrations of ATP, and they are particularly important in microglia.
P2Y receptors are classical seven-transmembrane-domain metabotropic receptors coupled to G-proteins. The P2Y1, P2Y6, P2Y11, P2Y12, P2Y13 and P2Y14 receptors are detected in the CNS, and all may be expressed in glial cells. Activation of glial P2Y receptors most commonly triggers InsP3-mediated release of Ca2+ from endoplasmic reticulum Ca2+ stores; P2Y1 receptors are important in astroglial Ca2+ signalling usually positively coupled to phospholipase C (PLC) and their activation triggers cytoplasmic Ca2+ signals and intercellular Ca2+ waves. The activation of P2Y receptors results in a transient increase in cytosolic Ca2+ that can last for seconds to minutes. A special role for the P2Y1 receptor subtype has been indicated in the propagation of astroglial Ca2+ waves. Ionotropic ATP receptors of the P2X class have been identified in astrocytes, oligodendrocytes, and in retinal Müller cells in situ. P2X receptors are generally rapidly desensitizing and their activation results in a transient ion current (generally inward Na+ current) lasting milliseconds; their functional role in glia remains undefined. Several types of P2X receptors are expressed in microglial cells; particularly important are P2X7 receptors, which are activated by high (>1 mM) ATP concentrations. Such a high ATP concentration can be achieved during neuronal damage and lysis and therefore P2X7 receptors may enable microglial cells to sense neuronal damage.
Activation of P2X7 receptors results in opening of a large channel, which allows passage of molecules up to 1 kDa; this property is somehow associated with microglial activation. P2X7 receptors play similar roles in pathology in Müller glia, Schwann cells, and oligodendrocytes, and possibly astrocytes. It is not clear that P2X7 receptors form pores in glia, and P2X7 receptors are not the only kinds of P2X receptors expressed by glia that are capable of pore-formation. In astrocytes, P2X7 receptors may mediate the release of ATP.
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