Expression and function coupling of P2Y1 and other P2Y nucleotide receptors in neurons. (360G-Wellcome-081706_A_06_Z)

P2Y receptors are G protein-coupled receptor targets for extracellular nucleotides. Some of these receptors are or appear to be present in the brain but their function therein is not well understood. By expressing different P2Y receptors in sympathetic neurons, we previously showed that their activation can variously modulate several neuronal ion channels. Recently we have localized one such receptor (the P2Y1 receptor) to hippocampal pyramidal neurons and shown that activation of this receptor reproduces one of the effects observed in sympathetic neurons (inhibition of M-type K+ channels), thereby increasing neuron excitability. We also have found that P2Y receptors can co-localize with each other and with scaffolding synaptic proteins We now propose to: (a) produce a detailed immunocytochemical map of P2Y1 receptor distribution, first in the hippocampus and then in some other brain structures; b) complete functional studies of P2Y1 effects on hippocampal pyramidal neurons; c) investigate the homo-dimerization of P2Y1 receptors in sympathetic and hippocampal neurons, and possible hetero-dimerization with other P2Y receptors, by FRET and functional readout; d) clarify the molecular mechanism of P2Y mediated effect on M-channels; and e) investigate the involvement of scaffolding proteins in neuronal P2Y receptor function.