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ATP released from neurons and astrocytes during neuronal activity or under pathophysiological circumstances is able to influence information flow in neuronal circuits by activation of ionotropic P2X and metabotropic P2Y receptors and subsequent modulation of cellular excitability, synaptic strength, and plasticity. In the present paper we review cellular and network effects of P2Y receptors in the brain. We show that P2Y receptors inhibit the release of neurotransmitters, modulate voltage- and ligand-gated ion channels, and differentially influence the induction of synaptic plasticity in the prefrontal cortex, hippocampus, and cerebellum. The findings discussed here may explain how P2Y1 receptor activation during brain injury, hypoxia, inflammation, schizophrenia, or Alzheimer's disease leads to an impairment of cognitive processes. Hence, it is suggested that the blockade of P2Y1 receptors may have therapeutic potential against cognitive disturbances in these states.

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We have previously identified the suramin analog 4,4Ј,4Љ,4ٞ-(carbonylbis(imino-5,1,3-benzenetriylbis(carbonylimino)))tetrakis-benzene-1,3-disulfonic acid (NF449) as a low nanomolar potency antagonist of recombinant P2X 1 receptors. Here, we characterize, by two-electrode voltage-clamp electrophysiology, three isomeric suramin analogs designated para-4,4Ј,4Љ,4ٞ-(carbonylbis(imino-5,1,3-benzenetriylbis (carbonylimino)))tetrakis-benzenesulfonic acid (NF110), meta- (3,3Ј,3Љ,3ٞ-(carbonylbis(imino-5,1,3-benzenetriylbis (carbonylimino)))tetra-kis-benzenesulfonic acid (NF448), and ortho- (2,2Ј,2Љ,2ٞ-(carbonylbis(imino-5,1,3-benzenetriylbis (carbonylimino)))tetra-kis-benzenesulfonic acid (MK3) with respect to their potency in antagonizing rat P2X receptor-mediated inward currents in Xenopus laevis oocytes. Meta, para, and ortho refer to the position of the single sulfonic acid group relative to the amide bond linking the four symmetrically oriented benzenesulfonic acid moieties to the central, invariant suramin core. NF448, NF110, and MK3 were Ͼ200-fold less potent in blocking P2X 1 receptors than NF449, from which they differ structurally only by having one instead of two sulfonic acid residues per benzene ring. Although the meta-and ortho-isomers retained P2X 1 receptor selectivity, the para-isomer NF110 exhibited a significantly increased activity at P2X 3 receptors (K i ϳ 36 nM) and displayed the following unique selectivity profile among suramin derivatives: P2X 2ϩ3 ϭ P2X 3 Ͼ P2X 1 Ͼ P2X 2 Ͼ Ͼ P2X 4 Ͼ P2X 7 . The usefulness of NF110 as a P2X 3 receptor antagonist in native tissues could be demonstrated by showing that NF110 blocks ␣␤-methylene-ATP-induced currents in rat dorsal root ganglia neurons with similar potency as recombinant rat P2X 3 receptors. Together, these data highlight the importance of both the number and exact location of negatively charged groups for P2X subtype potency and selectivity.P2X receptors constitute an abundant class of cell surface receptors that open an intrinsic pore that becomes permeable to small cations when exposed to extracellular ATP and related nucleotides (North, 2002). The seven known subunit isoforms, designated P2X 1 -P2X 7 , assemble into homotrimeric and heterotrimeric receptor channels (Nicke et al., 1998;Aschrafi et al., 2004;Mio et al., 2005), resulting in large receptor subtype diversity.Among the numerous sensory processes in which P2X receptors have been implicated, their involvement in nocicepThis research project is supported by the START-Program of the Faculty of Medicine, RWTH Aachen University (to R.H.); by a grant of the "Fonds der Chemischen Industrie" (to G.L.); and by the Deutsche Forschungsgemeinschaft grants GRK 677/1&2 (to M.U.K.), La 350/7-3 and GRK 137/3 (to G.L.), and Schm 536/6-1; FOR450, TP11 (to G.S.). Preliminary results of this work were presented as a meeting abstract: Hausmann R, Rettinger J, Kassack M, Lambrecht G, and Schmalzing G (2004) Characterization of the novel suramin analog NF110 as a potent P2X 3 receptor-selective antagon...

It is widely accepted that the most important ATP receptors involved in pain transmission belong to the P2X3 and P2X2/3 subtypes, selectively expressed in small diameter dorsal root ganglion (DRG) neurons. However, several types of the metabotropic ATP (P2Y) receptors have also been found in primary afferent neurons; P2Y1 and P2Y2 receptors are typically expressed in small, nociceptive cells. Here we review the results available on the involvement of P2Y receptors in the modulation of pain transmission.