Protein interactions and functional properties of P2Y1 nucleotide receptors in neurons (revised). (360G-Wellcome-090370_Z_09_Z)

£200,185

In previous and current work we have shown that the G-protein-coupled P2Y1 receptors (P2Y1Rs) for ATP are located in some CA1-3 pyramidal neurons, as is the scaffolding protein, NHERF-2, to which they can bind, and that they mediate inhibition of the neuronal M(Kv7)-current therein to increase neuronal firing. This is likely to be important because ATP has recently been reported to be constantly released onto central neurons by neighbouring astrocytes. We now propose: (1) to apply transgenic tec hnology to reveal the cellular location of P2Y1 and selected other identified P2Y subtypes in mouse brain in situ by pre-attached fluorophores; (2) to use these (with other approaches) to study (a) the neuronal function of P2Y1Rs by electrophysiology on identified P2YR-expressing neurons, (b) the sites of scaffolding protein NHERF-2 interaction with P2Y1Rs, (c) possible P2YR heterodimerization, and (d) to test the hypothesis (based on observations on hippocampal neurons and sympathetic neurons, which are devoid of NHERF-2) that NHERF-2 serves to confine P2Y1Rs (and possibly some mGluRs) to neuronal microdomains which facilitate coupling to M(Kv7)-channels and preclude coupling to Ca2+-channels and Kir(GIRK) K+-channels. If true, this will have major implications for neuronal receptor-ion channel regulation and pharmacology through membrane-linked microdomains.

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Grant Details

Amount Awarded 200185
Applicant Surname Brown
Approval Committee Molecular and Cellular Neuroscience Funding Committee
Award Date 2009-10-08T00:00:00+00:00
Financial Year 2009/10
Grant Programme: Title Project Grant
Internal ID 090370/Z/09/Z
Lead Applicant Prof David Brown
Other Applicant(s) Dr Alexander Filippov, Dr Joseph Simon, Prof Eric Barnard
Partnership Value 200185
Planned Dates: End Date 2012-09-30T00:00:00+00:00
Planned Dates: Start Date 2009-12-01T00:00:00+00:00
Recipient Org: Country United Kingdom
Region Greater London