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The Journal of Neuroscience, September 6, 2006, 26(36):9340-9348; doi:10.1523/JNEUROSCI.2635-06.2006

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Cellular/Molecular
Activation of P2Y₁ Nucleotide Receptors Induces Inhibition of the M-Type K⁺ Current in Rat Hippocampal Pyramidal Neurons

Alexander K. Filippov,¹ Roy C. Y. Choi,² Joseph Simon,² Eric A. Barnard,² and David A. Brown¹

¹Department of Pharmacology, University College London, London WC1E 6BT, United Kingdom, and ²Department of Pharmacology, University of Cambridge, Cambridge CB2 1PD, United Kingdom

Correspondence should be addressed to Dr. Alexander K. Filippov, Department of Pharmacology, University College London, Gower Street, London WC1E 6BT, UK. Email: a.filippov{at}ucl.ac.uk

We have shown previously that stimulation of heterologously expressed P2Y₁ nucleotide receptors inhibits M-type K⁺ currents in sympathetic neurons. We now report that activation of endogenous P2Y₁ receptors induces inhibition of the M-current in rat CA1/CA3 hippocampal pyramidal cells in primary neuron cultures. The P2Y₁ agonist adenosine 5'-[-thio]diphosphate trilithium salt (ADPS) inhibited M-current by up to 52% with an IC₅₀ of 84 nM. The hydrolyzable agonist ADP (10 µM) produced 32% inhibition, whereas the metabotropic glutamate receptor 1/5 agonist DHPG [(S)-3,5-dihydroxyphenylglycine] (10 µM) inhibited M-current by 44%. The M-channel blocker XE991 [10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone dihydrochloride] produced 73% inhibition at 3 µM; neither ADPS nor ADP produced additional inhibition in the presence of XE991. The effect of ADPS was prevented by a specific P2Y₁ antagonist, MRS 2179 (2'-deoxy-N'-methyladenosine-3',5'-bisphosphate tetra-ammonium salt) (30 µM). Inhibition of the M-current by ADPS was accompanied by increased neuronal firing in response to injected current pulses. The neurons responding to ADPS were judged to be pyramidal cells on the basis of (1) morphology, (2) firing characteristics, and (3) their distinctive staining for the pyramidal cell marker neurogranin. Strong immunostaining for P2Y₁ receptors was shown in most cells in these cultures: 74% of the cells were positive for both P2Y₁ and neurogranin, whereas 16% were only P2Y₁ positive. These results show the presence of functional M-current-inhibitory P2Y₁ receptors on hippocampal pyramidal neurons, as predicted from their effects when expressed in sympathetic neurons. However, the mechanism of inhibition in the two cell types seems to differ because, unlike nucleotide-mediated M-current inhibition in sympathetic neurons, that in hippocampal neurons did not appear to result from raised intracellular calcium

Key words: nucleotide receptors; P2Y receptors; hippocampus; pyramidal neurons; potassium channels; M-current

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Received March 14, 2006; revised July 31, 2006; accepted Aug. 3, 2006.

Correspondence should be addressed to Dr. Alexander K. Filippov, Department of Pharmacology, University College London, Gower Street, London WC1E 6BT, UK. Email: a.filippov{at}ucl.ac.uk

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