Chapter 9 - Impact of Ectoenzymes on P2 and P1 Receptor Signaling

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Abstract

P2 receptors that are activated by extracellular nucleotides (e.g., ATP, ADP, UTP, UDP, ApnA) and P1 receptors activated by adenosine control a diversity of biological processes. The activation of these receptors is tightly regulated by ectoenzymes that metabolize their ligands. This review presents these enzymes as well as their roles in the regulation of P2 and P1 receptor activation. We focus specifically on the role of ectoenzymes in processes of our interest, that is, inflammation, vascular tone, and neurotransmission. An update on the development of ectonucleotidase inhibitors is also presented.

Introduction

Extracellular nucleotides via P2 receptors and extracellular adenosine via P1 receptors are involved in a number of physiological processes (Abbracchio and Burnstock, 1998, Abbracchio et al., 2009, Di Virgilio et al., 2009, Hasko et al., 2008). The presence of nucleotides in the extracellular space not only arises as a result of cellular damage but also occurs in a controlled fashion by their secretion from activated cells (reviewed in Chapter 8). The information encrypted in nucleotide release is delivered into the cells through plasma membrane-bound ionotropic P2X (P2X1–7) and metabotropic P2Y (P2Y1,2,4,6,11–14) receptors. P2 receptor subtypes differ in respect to their selectivity toward nucleotides and are coupled to different intracellular signaling pathways. All P2X and P2Y11 receptors are activated by ATP; P2Y2 by ATP and UTP; P2Y1, P2Y12, and P2Y13 by ADP; P2Y4 by UTP; P2Y6 by UDP (and UTP in mouse; Kauffenstein et al., 2010a); and P2Y14 by UDP-glucose (Abbracchio et al., 2006). In addition, nucleotides can also activate other G protein-coupled receptors such as cysteinyl leukotriene receptor-1 and -2 (CysLT1R and CysLT2R), and GPR17 (Ciana et al., 2006, Mamedova et al., 2005, von Kugelgen, 2006).

Extracellular adenosine originates either from the catabolism of nucleotides by ectonucleotidases or from transport through SLC29 transporter formerly known as equilibrative nucleoside transporters (ENT; Colgan et al., 2006, Conde and Monteiro, 2004, Parkinson et al., 2005, Sowa et al., 2009, Zylka et al., 2008). Once outside the cell, adenosine activates G protein-coupled P1 receptors (A1, A2A, A2B, and A3) that exert physiological responses (Jacobson & Gao, 2006) often opposite to those activated by extracellular nucleotides through P2 receptors.

The activation of P2 and P1 receptors is regulated by ectoenzymes that either eliminate or produce extracellular nucleotides and adenosine. This review presents these enzymes and recent development about their described functions in three systems of our interest: inflammation, vascular tone, and neurotransmission. In addition, recent progress in the development of specific inhibitors for some of these enzymes is also presented.

Section snippets

Enzymes Metabolizing Extracellular Nucleotides

Extracellular nucleotides are generally metabolized by plasma membrane-bound enzymes whose active site faces the extracellular environment. These enzymes are also called with the more general term of ectoenzymes that reflects this property. Nucleotides can also be metabolized by exoenzymes that are secreted from cells or originate from ectoenzymes shedded from the plasma membrane either by a proteolitic cleavage by proteases or by the cleavage of their glycosyl phosphatidylinositol (GPI)

Ectonucleotidases and Ectokinases Control Cytokine Production

Cytokines are small soluble proteins produced by various cell types to mount immune responses. IL-8 is a key human cytokine involved in inflammatory recruitment of neutrophils (thus it is called a chemokine), cell proliferation and activation, and angiogenesis. In many cell types, the production of IL-8 is controlled by extracellular nucleotides (Ben Yebdri et al., 2009, Kukulski et al., 2007, Kukulski et al., 2009, Warny et al., 2001). A recent study has demonstrated that the endogenous

Note on Ectonucleotidase Inhibitor Development

The main challenge in designing ectonucleotidase inhibitors is to obtain molecules that would be isoform selective and would not affect P2 receptors. ARL-67156 (6-N,N-diethyl-β,γ-dibromomethylene-d-ATP) is one of the most used general ectonucleotidase inhibitors that inhibits either NTPDases or NPPs but does not affect P2 receptors. However, it must be used with caution as it is a weak competitive inhibitor of NTPDase1 and NTPDase3 that does not affect NTPDase2 (Iqbal et al., 2005, Lévesque et

Conclusion

This brief review shows that P2 and P1 receptor activation can be controlled by a complex network of ectoenzymes. There are some enzymes that hydrolyze nucleotides and others that resynthesize them. The product of one enzyme can be either a substrate or an inhibitor of another ectoenzyme and distinct ectoenzymes can compete for the same substrate which may lead to different products. However, numerous studies suggest that the majority of biological processes are regulated by few dominant

Acknowledgments

This work was supported by grants from the Canadian Institutes of Health Research (CIHR) to J. S. who was a recipient of a Junior 2 Scholarship from the Fonds de Recherche en Santé du Québec (FRSQ).

Conflict of Interest: The authors declare no conflict of interest.

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