Trends in Pharmacological Sciences
Adenosine and ATP: progress in their receptors' structures and functions
Section snippets
P2X receptors
P2X receptors are ATP-gated cation channels[1]. Alan North (Glaxo-Wellcome, Geneva) presented several lines of evidence supporting the proposed topology for P2X receptors of two transmembrane regions, a large extracellular loop and intracellular N and C termini. Asparagine residues introduced into the P2X2 receptor are only glycosylated when in the extracellular loop. Also, ATP evoked robust currents when a concatenated cDNA encoding a protein in which the C terminus of one P2X2 receptor is
P2Y receptors
In the past four years it has been proposed that numerous cloned receptors are members of the G protein-coupled family of P2Y receptors but, of these, only the P2Y1, P2Y2, P2Y4 and P2Y6 subtypes are widely accepted. Eric Barnard (Royal Free Hospital, London) showed that, at the chick p2y3 receptor, UDP is more potent than UTP, ADP or ATP. However, Ken Harden (University of North Carolina, Chapel Hill) suggested that this receptor is a species homologue of the P2Y6 receptor. Species homologues
Release and metabolism of ATP
Several speakers discussed the neurotransmitter functions of ATP. Frances Edwards (University College London) showed that ATP is a fast excitatory transmitter in the rat medial habenula. At high stimulation frequencies the failure rate of ATP-induced synaptic currents increases substantially. She suggested that synaptically released ATP is broken down to adenosine, which then acts on presynaptic receptors to depress further release of ATP. Klaus Starke (University of Freiburg) described the
Adenosine: sources and functions
Adenosine has been established as an important modulator of neuronal activity in the brain. Jürgen Schrader (Heinrich-Heine-Univer- sität, Düsseldorf) showed that intracellular formation of adenosine is directly related to cellular energetics and so is oxygen-dependent. Thus, hypoxia greatly increases adenosine production and release into the extracellular space via specific transporters, but only when energy metabolism is severely compromized. Several transporters have been cloned and they
A role for purines in pain?
Possible roles of purines in pain was a recurring feature of this meeting. Tony Yaksh (University of California, San Diego) discussed evidence that spinal adenosine A1 receptors inhibit painful stimuli. In contrast, A2A receptors present on nociceptive nerve endings enhance their activity. Thus, the A2A receptor knockout mice described by Parmentier are hypoalgesic.
Geoff Burnstock (Autonomic Neuroscience Institute, London) outlined a model for the involvement of ATP released from various cell
Concluding remarks
Adenosine and its receptors have long led the field of purine research and here we were given greater detail of many of their functions, some of which were confirmed in receptor knockout mice. Relatively less is known about the functions of ATP and P2 receptors, due to the historical lack of selective ligands. Now with the cloning of two large families of P2 receptors, many more possible functions are beginning to be revealed. Finally, the actions of the poor cousins of this field, pyrimidines,
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