The Purines Atp And Adenosine

ATP (ADENOSINE TRIPHOSPHATE)

For many years ATP has been clearly established as an important intracellular mediator of neuronal function and the provider of cellular energy. The concept that it may also be a neurotransmitter is more recent. It stems from the finding of Burnstock and his colleagues that it was the mediator of the non-adrenergic, non-cholinergic (so-called NANC) innervation of smooth muscle in the intestine and bladder (see Burnstock et al. 1970). Generally ATP is a co-transmitter with a wide range of other NTs and while its role may usually be secondary to them, it actually appears in some sympathetically innervated tissue to mediate the initial contraction of smooth muscle rather than the maintained tone. Structurally it consists of an adenine ring, a ribose element and a triphosphate chain (Fig. 13.1).

ATP certainly fulfils the criteria for a NT. It is mostly synthesised by mitochondrial oxidative phosphorylation using glucose taken up by the nerve terminal. Much of that ATP is, of course, required to help maintain Na+/K+ ATPase activity and the resting membrane potential as well as a Ca2+ATPase, protein kinases and the vesicular binding and release of various NTs. But that leaves some for release as a NT. This has been shown in many peripheral tissues and organs with sympathetic and parasympathetic innervation as well as in brain slices, synaptosomes and from in vivo studies with microdialysis and the cortical cup. There is also evidence that in sympathetically innervated tissue some extracellular ATP originates from the activated postsynaptic cell. While most of the released ATP comes from vesicles containing other NTs, some

Neurotransmitters, Drugs and Brain Function. Edited by R. A. Webster ©2001 John Wiley & Sons Ltd

Figure 13.1 Chemical structures of, and relationship between, adenosine and adenosine 5'-triphosphate (ATP). Adenosine contains an adenine ring and ribose component. Phosphorylation of the latter's termial (C5) hydroxy with three phosphate groups gives ATP

may be stored alone or come directly from the cytoplasm. The extracellular ATP is broken down to adenosine by ecto ATPase.

Unfortunately techniques do not exist for demonstrating purinergic nerves but purinergic receptors have been established. They are divided into two broad groups, Pi and P2. The former tend to be located presynaptically, are activated mainly by adenosine and have been reclassified accordingly as Ai and A2 (and now A3). The latter, which respond to ATP, are postsynaptic and as with many other NTs can be divided into two families. Those linked to a fast ionotrophic effect are classified as P2x, with currently six subtypes and those with slow metabotropic effects as P2y with seven subtypes. It is the P2x receptors that mediate the primary transmitter effects of ATP. They have been most studied and while all may be found in the CNS, P2x2, P2x4 and P2x6 predominate. A schematic representation of a possible ATP (purinergic) synapse is shown in Fig. 13.2.

The role of ATP in the neural control of smooth muscle function is now, as indicated above, well established but its central actions are less clear and have only been studied closely in two areas. In slices of rat medial habenula the synaptic currents, recorded with the whole-cell patch-clamp technique that were evoked by electrical stimulation in the presence of both glutamate and GABA antagonists, were inhibited by the P2x (P2x2 preferred) antagonist suramin and by a^-me-ATP an agonist that desensitises some P2x receptors but not normally the P2x2 form. Thus while it is difficult to characterise the precise receptor subunit involved this provides strong evidence for a neurotransmitter

Oxidative

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Figure 13.2 Schematic representation of a possible ATP, purinergic, synapse. The effects of ATP, synthesised intraneuronally by mitochondrial oxidative phosphorylation from glucose, on various neuronal ATPases, are shown together with its actions as a conventional neurotransmitter acting k> at postsynaptic P2 and presynaptic Pj receptors role for ATP, although it is not known to what extent blocking P2x2 receptors modifies synaptic transmission when the amino acid receptors are functional. Interestingly the currents mediated by P2x receptor activation are smaller and decay much more slowly than those which characterise glutamate's activation of AMPA receptors but are larger and faster than those mediated by its NMDA receptor. Thus in contrast to NMDA currents, those for ATP are less likely to be involved in the temporal integration of synaptic activity (Gibb and Halliday 1996). The P2x receptor is also linked to control of calcium rather than sodium flux and its subunits have two transmembrane domains compared with the four of glutamate's AMPA and ACh's nicotinic receptor.

This above effect of ATP has also been demonstrated on neurons in lamina II of the dorsal horn in transverse slices of rat cord. Here blockade of glutamate GABA and glycine effects left a current, produced by local tissue or dorsal root stimulation which was again sensitive to the P2x2 antagonist suramin (Bardoni et al. 1997) (Fig. 13.3). Although only 5% of neurons showed this response, the expression of P2x receptors there and the long established release of ATP from the peripheral terminals of dorsal root ganglia neurons and presumably therefore the central ones, have obviously raised interest in ATP being yet another NT involved in the mediation of afferent painful nociceptive stimuli (Chapter 21).

Thus the neurotransmitter role of ATP is well established in the periphary and also in sensory systems but its importance in the CNS remains to be elucidated (see Burnstock 1996). That requires the development of more specific antagonists and methods of mapping its location. The strong linkage of its P2x receptors to calcium currents may also provide a role for ATP in more long-term effects such as plasticity and neuronal development and death.

ADENOSINE

This is not considered to be a neurotransmitter but it may be an important modulator of neuronal activity through its various receptors, Ai, A2 and A3. In addition to its ability

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