Recombinant P2Y receptors: the UCL experience

The beginning of the last decade heralded three important and sequential de velopments in our understanding of cell-to-cell signalling by extracellular ATP via its cell surface receptors. thr P2 purinoceptors. One major develo pment in ATP signalling culminated in a timely review in 1991, when it was established in the dearest of terms that ATP receptors exploited discrete s ignal transduction pathways (Dubyak, G.R., 1991. Signal transduction by P2- purinergic receptors for extracellular ATP. Am. J. Respir. Cell. Mel. Biol. 4, 295-300; and later in Dubyak, G.R., El-Moatassim, C., 1993, Signal tran sduction via P2-purinergic receptors for extracellular ATP and other nucleo tides. Am. J. Physiol. 265, C577-C606). Henceforth, it was universally ackn owledged that some P2 purinoceptors interacted with heterotrimeric G-protei ns to activate intracellular signalling cascades (metabotropic ATP receptor s), whereas others contained intrinsic ion-channels (ionotropic ATP recepto rs). A second key development can be traced to 1992, from the discovery tha t ATP receptors were involved in excitatory neurotransmission in the CNS an d PNS (Edwards, F.A., Gibb, A.J., Colquhoun. D., 1997. ATP receptor-mediate d synaptic currents in the central nervous system. Nature 359, 144-147; Eva ns, R.J., Derkach, V., Surprenant, A., 1993. ATP mediates fast synaptic tra nsmission in mammalian neurons. Nature 357, 503-505; Silinsky, E.M., Gerzan ich, V., Vanner, S.M., 1992. ATP mediates excitatory synaptic transmission in mammalian neurones. Br. J. Pharmacol., 106, 762-763). Thereafter, it was accepted that ATP could play a neurotransmitter and/or modulatory role thr oughout the entire nervous system. The third key development stemmed from t he isolation of a cDNA, from chick brain, encoding a metabotropic ATP recep tor (Webb, T.E., Simon, J., Krishek B.J., Bateson, A.N., Smart, T.G., King, B.F., Burnstock, G., Barnard, E.A., 1993. Cloning and functional expressio n of a brain G-protein-coupled ATP receptor. FEES Lett. 324, 219-225). The cloning of a membrane protein serving as an ATP receptor ignited a widespre ad international interest in purinergic signalling. Investigators at Univer sity College London (UCL) - colleagues and associates of Geoffrey Burnstock were at the forefront of this rapid phase of discovery. In this review, we highlight the UCL experience when the fields of molecular biology, physiol ogy and cell biology converged to help advance our understanding of ATP as an extracellular signalling molecule. (C) 2000 Elsevier Science B.V. All ri ghts reserved.