Fig. 1.

(A) Action at P2YRs of nucleotides released from cells (e.g., ATP, UTP, and UDPG) and their conversion outside the cell to 5′-diphosphates, which act at different P2YRs, and/or to 5′-monophosphates, which are inactive (inact.). 5′-nucleotidase catalyzes the final conversion of AMP to adenosine, which acts at its own set of four GPCRs (adenosine A₁, A_2A, A_2B, and A₃ receptors). There is a redundancy of ligands that activate various P2YR subtypes. The nucleotides may act as full agonists (green arrows) or variably partial agonists and antagonists (orange arrow). EC₅₀ or IC₅₀ values (µM) at human P2YRs from measurement of adenylate cyclase or phospholipase C activity are indicated in italics. Weaker interactions, such as UDP, as an agonist of P2Y₂R (∼10) or P2Y₆R (16) are not shown. The enzymatic conversions are catalyzed by ecto-nucleotidases (blue arrows): (a) ecto-nucleoside triphosphate diphosphohydrolases (CD39s) act on either 5′-triphosphates or 5′-diphosphates; (b) ecto-nucleotide pyrophosphatase/phosphodiesterases convert 5′-trimonophosphates to 5′-monophosphates; (c) NPP1 and NPP3 hydrolyze UDPG to produce UMP. (B) Naturally occurring dinucleotides (n = 2–7; B is a nucleobase) are shown schematically and described in detail later in the text. The dinucleotides, such as Up₄A and Ap₄A, may either act directly on P2YRs, in some cases, or be converted by ecto-nucleotide pyrophosphatase/phosphodiesterases to active mononucleotides, such as ADP. P2YR potencies of simple dinucleotides are reported (Shaver et al., 2005).