Pharmacological characterisation of the hP2Y₁₁ and XlP2Y₁₁ receptors
Extracellular nucleotides and nucleosides are important signalling molecules that exert a diverse range of physiological responses throughout the body. These chemical messengers often transduce their effects through interaction with specific cell surface receptors called purinoceptors. The P2Y purinoceptor family binds extracellular nucleotides, principally ATP, ADP, UTP and UDP. Conformational change of the P2Y purinoceptors upon ligand binding conveys a signal to intracellular heterotrimeric G proteins, which are activated, transducing the signal further downstream by acting at different effector enzymes to influence second messenger production. In this thesis I present the first pharmacological characterisation of a non-mammalian P2Y11 receptor orthologue, Xenopus laevis P2Y11 (XlP2Y11), and extend the pharmacological profile of the human P2Y11 receptor (hP2Y11). Second messenger assays were employed to record the intracellular cyclic AMP (cAMP) accumulation and Ca2+ mobilisation generated by both the human and Xenopus laevis P2Y receptors in response to various P2Y agonists and antagonists. In a manner similar to its human orthologue, I have shown that XlP2Y11 is activated by nucleotides and nucleotide analogues, mobilising calcium from intracellular stores, and increasing cAMP production through the activation of adenylyl cyclase. When compared to previously published data, XlP2Y11 exhibits a novel rank order of agonist and antagonist potency, revealing a receptor functionally similar but pharmacologically distinct from both the human and canine P2Y11 receptor orthologues (hP2Y11 and cP2Y11).