P2Y Receptors: Focus on Structural, Pharmacological and Functional Aspects in the Brain

W.      Fischer; U.      Krugel

doi:10.2174/092986707782023695

Abstract

Purine and pyrimidine nucleotides have been identified as potent extracellular signalling molecules, acting at two classes of cell surface receptors, ionotropic P2X and metabotropic P2Y receptor (-R) types. Hitherto eight subtypes of the P2Y-R family have been cloned from mammalian species that exhibit sensitivity to the adenine nucleotides ATP/ADP (P2Y1,11,12,13), the uracil nucleotides UTP/UDP (P2Y2,4,6 or UDP-glucose in the case of P2Y14) or both adenine and uracil nucleotides (P2Y2). The P2Y-Rs are G proteincoupled receptors activating phospholipase C via Gαq/11 protein and stimulating or inhibiting adenylyl cyclase via Gαs and Gαi/o proteins, respectively. These receptors may activate distinct signalling cascades. Although classical models predict that P2Y-Rs exist in the cell membrane as monomers, homo- or heterodimeric assemblies may be generated. Interactions with certain ion channels or ligand-gated receptors as well as the co-localization of several receptor subtypes in the same cell provide the basis for a high functional diversity. The proteins for various P2Y-Rs are expressed early in the embryonic brain and are broadly distributed on both, neurons and astroglial cells. P2Y-R involvement in the regulation of normal physiological processes on the cellular level or in vivo, such as modulation of transmitter release, generation of astroglial Ca2+ waves, in diverse effects on behavioural functions and in the etiopathology of neurodegenerative diseases, are discussed and own data are presented. However, the exact understanding of the role of individual P2Y-R subtypes is still limited. Concerning the potentially important functions of P2Y-Rs, there is a strong need to develop stable, lipophilic and subtypeselective P2Y-R ligands, which may open new therapeutic strategies.

Keywords: Astrocytes, ATP, behaviour, neurons, neurodegenerative diseases, purinergic signalling, synaptic transmission

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