P2Y Receptors: Structure and Function
Following the finding that nucleotides act as extracellular signalling molecules by interaction with cell surface transmembrane P2 receptors, it has now been recognised that this mode of regulation is widespread, exerting a ubiquitous influence on physiol
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P2Y Reeeptors: Strueture and Funetion M.R. BOARDER and T.E. WEBB
A. Introduction Following the finding that nucleotides act as extracellular signalling molecules by interaction with cell surface transmembrane P2 receptors, it has now been recognised that this mode of regulation is widespread, exerting a ubiquitous influence on physiological function. Indeed, P2 receptors are present on most cells in the body (RALEVIC and BURNSTOCK 1998) P2 receptor regulation via disparate cell types is mirrored by the diversity of cellular responses that these receptors elicit on activation by endogenous nucleotides. This diversity in turn comes, in part from multiple P2 receptors, and in part from different responses to activation of the same receptors in different cell types. P2 receptors are subdivided into P2X receptors with intrinsic ion channels and G protein-coupled P2Y receptors (ABBRACCHIO and BURNSTOCK 1994; FREDHOLM et al. 1997). The wide spread distribution of multiple P2Y receptor subtypes represents an important challenge in characterising and classifying this subfamily of receptors in order to understand the manner in which their activation by native extracellular nucleotides gives rise to cognate cellular responses. It has been evident for some time that different P2Y receptor-subtypes can give rise to distinct cellular responses, even when two subtypes are located on the same cell, and even when both are coupled to a similar level of stimulation of phospholipase C. In this chapter, the relationships between the molecular and pharmacological properties of these P2Y receptors is discussed, as well as the contribution of structural diversity to the contral of intracellular signalling pathways to understand at the cellular level how the different receptors of the P2Y subfamily generate appropriate functional responses. To pursue this objective, an overview of some current issues concerning the P2Y receptors is provided.
M. P. Abbracchio et al. (eds.), Purinergic and Pyrimidinergic Signalling I © Springer-Verlag Berlin Heidelberg 2001
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M.R. BOARDER and T.E. WEBB
B. P2Y Receptors I. G Protein-Coupled Receptors P2Y receptors are members of the G protein-coupled (GPCR) superfamily of heptahelical receptors. These have in common an extracellular aminoterminus, followed by seven transmembrane domains, and an intracellular carboxy-terminus (Fig. 1). The native nuc1eotide agonists are highly charged moleeules which dock with aspects of the extracellular and transmembrane domains, causing a change in the interface between the receptor and G proteins located at the intracellular face of the cell membrane. The a subunit of the heterotrimeric G protein sheds GDP and takes up GTP, and then dissociates to generate lXoTP and ßysubunits, which have the potential to control effector proteins. In P2Y signalling, these effector proteins are often assumed to be the enzyme phospholipase C and adenylate cyc1ase, but mayaiso inc1ude ion channels and other signalling proteins (see Sect.E). These primary signalling events are initiall
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