Old Molecule, New Roles: Neurotransmission by ATP

Para Ghildyal, D Palani & Rohit Manchanda, School of Biosciences & Bioengineering

 

Adenosine 5'-triphosphate (ATP) has long been known to be responsible for the storage and provision of metabolic energy in biological organisms. However, in the past few decades an unexpected extra-cellular function of ATP has emerged. For long, it had been postulated that ATP is released from nerves and it acts upon target cells in order to transmit signals across synapses (the space between nerve cells and target cells), i.e. as a synaptic neurotransmitter. In mediating this function, ATP joined the ranks of neurotransmitter molecules such as: the better-known acetylcholine (ACh), noradrenaline (NA), serotonin (5-HT), dopamine (DA), and gamma-amino butyric acid (GABA). It was in the late sixties and early seventies, with the discovery and elucidation of "purinergic" nerves, that the possible role of ATP as a neurotransmitter was propounded.

         Over the ensuing three decades, neurotransmitter functions of ATP have been the subject of intensive scientific scrutiny. It has been shown to act via specialized membrane proteins called the purinergic receptors. These receptors are of two types – the P2X which are the fast acting ligand-gated receptors and the P2Y which are slower acting G-protein linked metabotropic receptors. ATP thus transmits signals carried by the nerves via the P2X receptors in a few milliseconds (fast neurotransmission), and by the P2Y receptors over a few hundreds of milliseconds to seconds (slow neurotransmission) in a variety of systems in the brain, spinal cord and other peripheral organs.

         Studies on the neurotransmitter function of ATP led to the discovery of an even more interesting phenomenon. Individual neurons of the autonomic nervous system were found to contain and release ATP along with a classical neurotransmitter like ACh and NA, thus giving rise to the concept of "Co-transmission". Co-transmission has been described as the co-localization and co-release of two or more neurotransmitters upon nerve stimulation from the same nerve terminals, to act on the post-synaptic cells to carry out the process of neurotransmission. The actions of co-transmitters on the post-synaptic cells have been reported to be either synergistic or antagonistic. Indeed, studies on purinergic co-transmission in the CNS have given rise to interesting insights on how transmitters might interact to produce novel patterns of postsynaptic activation, unobtainable by either transmitter alone.

Research at IIT Bombay
This novel feature of co-transmission by ATP along with other neurotransmitters alters our concept of the biophysics and biochemistry of neurotransmission at these synapses. In the nerve-muscle physiology laboratory of the School of Biosciences & Bioengineering, we are investigating various aspects of both these issues, i.e. the involvement of ATP as a synaptic neurotransmitter and its significance in co-transmission.

         For any molecule to be classified as a neurotransmitter there are certain criteria that need to be fulfilled. For example, for every neurotransmitter, its synthesis and storage in the nerve terminals have to be demonstrated. Further, it should be shown that the proposed neurotransmitter is released from the nerve terminal on nerve stimulation. External application of a neurotransmitter should mimic the response to nerve stimulation, and finally, an effective system for the inactivation of the neurotransmitter molecule from the synapse should be present........ more on next page