Neuronal synthesis, storage and release of ATP

Adenosine 5′-triphosphate (ATP) is a ubiquitous substance in the central and peripheral nervous system. Nerve terminal ATP is generated from ADP, during glycolysis, citric acid cycle and predominantly by oxidative phosphorylation in the mitochondria. The adenine ring is synthesized via de-novo purine biosynthesis, and also by purine salvage pathways. The main regulator of ATP synthesis is ADP, the signal of the actual energy state of the neuron. It inhibits (negative feedback) its own synthesis and also regulates mitochondrial oxidative phosphorylation.

Storage of ATP has been shown in all types of synaptic vesicles and it can also be found in the cytoplasm in millimolar range. ATP can be co-packaged with other neurotransmitters such as acetylcholine and noradrenaline and may be stored in purinergic vesicles and, perhaps, in purinergic nerve endings. Various treatments can alter vesicular composition, and hence, vesicular neurotransmitter/ATP ratio.

There is now wide acceptance that ATP is released stimulation-dependently from nerve endings of a number of isolated tissues and preparations upon depolarizing stimuli. In addition to presynaptically derived ATP, ATP release from activated target cells in response to the action of primary transmitter on postsynaptic receptors also forms a significant contribution to neuronal outflow in several tissues. As for the possible role of intraterminal ATP pools in the release process, recent observations support the view that ATP is released as a genuine cotransmitter, or as a principal purinergic neurotransmitter in an exocytotic way, but also indicate the involvement of other neuronal pools of ATP in the release, such as carrier-mediated release from the cytoplasm.