Photoaffinity labelling of the adenosine nucleotide transporter of cholinergic vesicles.

ATP is generated primarily in the mitochondria and during anaerobic glycolysis to fuel energy-consuming processes of animal organisms. ATP and the enzymes necessary for its function and hydrolysis are therefore also present in neuronal cells. Besides the energy demand for the biosynthetic centre, the cell body, a great deal of energy is used, as in other cells, in establishing a Na+/K+-gradient across the plasma membrane, which allows the propagation of action potentials. However, there may be a wider involvement of ATP and other purines in neuroregulatory mechanisms. Chemical neurotransmission is the basic mechanism for transfer of information between nerves, between nerves and muscles, glands and other receptor organs. To date, a still growing number of chemical neurotransmitter substances have been detected. They include small molecules such as acetylcholine, adrenaline, noradrenaline, dopamine, serotonin, or amino acids like ~-amino butyric acid (GABA), glutamate, glycine and even larger molecules, the neuropeptides. In the central and peripheral nervous system purines have been found to modulate the release of transmitter, to be involved in the regulation or control of adenylate cyclase activity, and to influence receptor sensitivity (for review see Stone, 1981). A functional role for ATP as neurotransmitter has been postulated (Holton and Holton, 1954; Burnstock, 1972, 1985). Recent evidence from several groups suggests that ATP acts as a co-transmitter with noradrenaline in sympathetic nerves supplying the guinea-pig vas deferens (Meldrum and Burnstock, 1983; Sneddon et al., 1982; Sneddon and Westfall, 1984; Stj/irne and Astrand, 1984). The role of ATP as the primary neurotransmitter in so-called 'purinergic' nerves remains unresolved, but it has been reported that certain primary afferent fibres may utilize ATP to excite neurones in the sensory regions of the brain, as well as in the spinal cord (Jahr and Jessell, 1983; Fyffe and Perl, 1984). If there are metabolic mechanisms common to all transmitter-releasing synapses, one would expect, as originally developed for cholinergic transmission, that transmitter molecules are packaged in storage vesicles. Upon stimulation, vesicle contents are released to evoke a specific postsynaptic reaction. Re-uptake mechanisms and transmitter synthesis pathways allow the re-utilization of transmitter molecules. In the case of acetycholine and the biogenic amines this has been clearly demonstrated. Similarly, substance P and the enkephalins have been shown to reside within storage vesicles. It has also long been known that ATP is associated with synaptic vesicles and other secretory granules including chromaffin granules, noradrenergic vesicles and serotonin-containing granules from blood platelets. However, it is difficult to obtain unequivocal answers to questions like: is the release of a putative transmitter substance directly correlated with specific neuronal activities? Is there a chemical signal which mediates the response of a postsynaptic receptor cell or is the function of such a substance to modulate undescribed presynaptic release mechanisms which could lead to activation or inhibition of neuronal communication