Introduction 1 2A 2B 3 1 2 2A 2A 1 3 4 6 Adenosine and analogues 1 3 5 6 5 6 1 1 5 7 8 9 10 Fig. 1 Chemical structures of the endogenous ligand adenosine and the antagonist caffeine  Occurrence and physiological functions of adenosine receptors The adenosine receptors are widespread throughout the body and exert many different functions both in the CNS and in the periphery. 1 1 1 5 6 1 1 1 5 6 11 2A 1 5 6 2A 1 2A 5 6 2A 12 14 2B 2B 5 6 2B 2B 5 6 3 3 15 3 1 3 5 6 16 3 5 16 3 6 3 3 17 Signal transduction of adenosine receptors G protein-coupling and second messengers 18 s i 0 + q/11 12 olf 19 21 18 1 \documentclass[12pt]{minimal}
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\begin{document}$${\text{G}}_{{{\text{i}}\alpha }} $$\end{document} 3 q/11 5 6 24 Desensitization and internalization—general principles and players Mechanisms to dampen GPCR signalling exist at every level in the cell. In this section attention will be paid to the underlying principles of desensitization and internalization and the protein partners involved in these processes. Receptor localization 1 2 25 26 Desensitization 3 2 19 25 27 28 Fig. 2 a b \documentclass[12pt]{minimal}
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\begin{document}$$\beta \gamma  = {\text{G}}_{{{\text{i}}\beta \gamma }} $$\end{document} L GRK P β-arr E PKA PKC  Internalization 31 19 25 31 Internalization pathways 3 19 25 26 Fig. 3 25 a b c d L green triangle dotted blue lines solid pink lines  Function of lipid rafts/caveolae 32 19 25 26 33 G protein-coupled receptor kinases (GRKs) 31 31 β-Arrestins 19 25 27 28 31 34 31 Dampening adenosine receptor signals In this section we will discuss the evidence for and mechanisms of desensitization and internalization of the four adenosine receptor subtypes. For each receptor we will first summarize results from in vitro, ex vivo and in vivo studies. This will be followed by a more biochemical approach in which we will focus on the molecular mechanisms of adenosine receptor desensitization and internalization by paying attention to the role of accessory proteins, the influence of receptor mutations, etc. We will refer to earlier seminal publications, but mostly focus on more recent evidence for adenosine receptor desensitization and internalization. 1 Cellular and physiological studies 1 1 1 1 2A 1 35 36 1 37 1 1 38 1 3 3 3 \documentclass[12pt]{minimal}
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\begin{document}$${\text{G}}_{{{\text{i}}\alpha }} $$\end{document} 45 Molecular mechanisms As discussed in the general introduction to this review, receptor posttranslational modifications, receptor phosphorylation, recruitment of arrestins and the formation of clathrin-coated pits are elements of the molecular machinery of desensitization and internalization. In addition, other potential protein partners in the two processes have been studied for the various adenosine receptor subtypes, which will also be discussed. Effect of receptor posttranslational modifications on desensitization and/or internalization 1 309 1 46 47 GRKs and arrestins 1 1 1 37 47 1 36 1 \documentclass[12pt]{minimal}
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\begin{document}$${\text{G}}_{{{\text{i}}\beta \gamma }} $$\end{document} 48 1 Other protein partners 1 1 49 50 1 51 1 1 49 52 1 1 1 1 1 50 51 1 1 1 1 1 1 1 53 Receptor-receptor interactions 3 3 1 3 54 2A 1 2A 1 1 2A 1 1 55 56 1 2A 2A 1 56 1 9 9 1 \documentclass[12pt]{minimal}
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\begin{document}$${\text{G}}_{{{\text{s}}\alpha }} $$\end{document} 59 2A 2B 60 61 1/2 2A 62 2A 2A 2A 3 1/2 62 2A 2A 2A 2A 2A 50 63 2A 1 64 2A 2A 2A 2A 1 65 2A 66 45 2 2 s s 67 antagonist 2A s 67 2B Molecular mechanisms Effect of receptor C terminus on desensitization and/or internalization 2A 2A 4 GRKs and arrestins 2A 4 2A 2B 2A 2B 2A 2A 68 2A 60 2A 2A 69 70 2A 2A 2A 71 Other protein partners 2A 72 71 73 Receptor-receptor interactions 2A 2 74 2A 2 2 2A 75 2 2A 76 2 77 2A 2 2 2 78 2A 1 1 2A 79 2B Cellular and physiological studies 2B 2B 2B 80 2B 2B 2B 80 2A 2B 2B 60 61 2A 2B 2A 2B 2A 2B 2A \documentclass[12pt]{minimal}
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\begin{document}$${\text{G}}_{{{\text{s}}\alpha }} $$\end{document} 2A 59 2B 2B 2B 81 1/2 2B 2A 82 2B 2B 2B 2B 83 84 2B s 84 2B Molecular mechanisms Effects of receptor mutations on desensitization and/or internalization 2B 2B 85 2B 330 2B 328 325 329 326 326 2B GRKs and arrestins 2B 2A 2B 68 2B 60 2B 2B 80 2B 61 2B 2B 2B 82 2A 2B 2B 2B 2B 86 2B 2 2 27 3 3 3 3 3 3 3 87 Cellular and physiological studies 3 2+ 88 3 3 3 3 89 3 i 3 s 90 3 ½ ½ 91 3 3 3 3 3 3 3 3 3 92 3 93 3 3 3 3 3 3 3 3 94 3 3 3 h/h 3 3 3 h/h 3 3 2+ 3 h/h 3 3 95 Molecular mechanisms Receptor phosphorylation, GRKs and arrestins 3 96 91 307 318 319 3 318 319 318 319 318 319 302,305 3 3 3 318 1 3 37 3 3 1 3 3 3 3 3 97 3 3 3 98 3 3 47 Conclusions 1 2A 2B 2A 1 3 3