### A. Overview

Extracellular purines (adenosine, ADP, and ATP) and pyrimidines (UDP and UTP) are important signaling molecules that mediate diverse biological effects via cell-surface receptors termed purine receptors. In this review particular emphasis is placed on the discrepancy between the

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Receptors for Purines and Pyrimidines

Four adenosine receptors have been cloned and characterized from several mammalian species. The receptors are named adenosine A(1), A(2A), A(2B), and A(3). The A(2A) and A(2B) receptors preferably interact with members of the G(s) family of G proteins and the A(1) and A(3) receptors with G(i/o) proteins. However, other G protein interactions have also been described. Adenosine is the preferred endogenous agonist at all these receptors, but inosine can also activate the A(3) receptor. The levels of adenosine seen under basal conditions are sufficient to cause some activation of all the receptors, at least where they are abundantly expressed. Adenosine levels during, e.g., ischemia can activate all receptors even when expressed in low abundance. Accordingly, experiments with receptor antagonists and mice with targeted disruption of adenosine A(1), A(2A), and A(3) expression reveal roles for these receptors under physiological and particularly pathophysiological conditions. There are pharmacological tools that can be used to classify A(1), A(2A), and A(3) receptors but few drugs that interact selectively with A(2B) receptors. Testable models of the interaction of these drugs with their receptors have been generated by site-directed mutagenesis and homology-based modelling. Both agonists and antagonists are being developed as potential drugs.

https://pharmrev.aspetjournals.org/content/pharmrev/53/4/527.full.pdf

International Union of Pharmacology. XXV. Nomenclature and Classification of Adenosine Receptors

Publisher Summary This chapter describes the role of adenosine in brain function Adenosine is an endogenous neuromodulator that influences many functions in the central nervous system (CNS) The levels of adenosine increase when there is an imbalance between the rates of energy use and the rates of energy delivery Increased neuronal activity, and hypoxia or ischemia results in elevated levels of adenosine Adenosine receptors (ARs) were based on the ability of methylxanthines, such as theophylline and caffeine to act as antagonists The two receptors, A1 and A2, inhibit and stimulate adenylyl cyclase respectively The functions of ARs include: (1) regulation of nerve activity, (2) regulation of transmitter release, (3) interaction with other transmitter systems, and (4) various other functions Increased extracellular adenosine in response to ischemia and hypoxia acts as a neuro-protectant during cerebral ischemia and other neuronal insults ARs (A 1 Rs and A 2A Rs) are expressed at moderate to high levels in the brain areas enriched with dopaminergic innervation, thus providing an anatomical basis for interaction between these neurotransmitter systems Different features of the phenotypes provide clues to the roles of defects in AR genes in human disease The chapter discusses the roles of adenosine A 2A receptors in neurodegenerative disorders and ARs in psychiatric disorders Caffeine is used to improve wakefulness and the main actions of caffeine are mediated by brain ARs Adenosine might be an endogenous regulator of sleep–wake cycles, as adenosine analogs induced a sleep-like state In addition, ARs may play many roles in pathways that contribute to pain Clearly much additional work is needed to pinpoint the sites and mechanisms of action, as well as the roles in chronic pain states

Adenosine and Brain Function

Distribution, biochemistry and function of striatal adenosine A2A receptors

Purinergic signalling: From normal behaviour to pathological brain function

Several lines of evidence suggest an involvement of adenosine A2a receptor (A2aAR) mediated adenosinergic neuromodulation in the etiopathogenesis of schizophrenia We therefore perfomed a systematic mutation scan of the complete coding region of the human A2aAR gene in a sample of 42 schizophrenic patients We detected one rare naturally occurring receptor variant (Gly-340-Ser) and two silent mutations (405C/T and 1083C/T) To our knowledge the Gly-340-Ser substitution is the first naturally occurring molecular variant of the A2aAR identified Determining the frequency of the three variants in 42 unrelated healthy controls, we observed a significant trend towards an overrepresentation of the 1083T variant in patients when compared to controls (p=0041) This trend was followed up in a large independent replication sample However, we were not able to confirm the original trend in the second sample (p=0367) The Ser-340 variant was found in a single schizophrenic individual Investigation of the patient's family revealed independent segregation between the Ser-340 variant and psychiatric illness Our data suggest that genetically determined structural variation of the A2aAR does not play a major role in the development of schizophrenia

Human adenosine A2a receptor (A2aAR) gene: systematic mutation screening in patients with schizophrenia

Anxiety disorders have been reported to be associated with low-voltage EEG (LVEEG). Some cases with LVEEG (approximately 1/3) have been linked to chromosome 20q13.2-q13.3. In the same chromosomal region, the gene for the neuronal nicotinic acetylcholine receptor α4 subunit (CHRNA4) has been located. We therefore tested the hypothesis that polymorphisms in the CHRNA4 gene show an allelic association with panic disorder. We examined the allele frequencies of three different CHRNA4 polymorphisms in patients with panic disorder and in healthy controls. No significant differences in the allele frequencies of these three polymorphisms were noted. This study does not support an association between panic disorder and the CHRNA4 gene. Am. J. Med. Genet. 74:199–201, 1997. © 1997 Wiley-Liss, Inc.

Neuronal nicotinic acetylcholine receptor α4 subunit (CHRNA4) and panic disorder: An association study

In the present study we sought to identify genetic variation in the adenosine A1 receptor (A1AR) gene on chromosome 1q31-32.1, which through alteration of protein function or level of expression might contribute to the genetic predisposition to bipolar affective disorder. We performed a systematic mutation scan of the whole coding sequence as well as 5′ and 3′ untranslated regions by means of single-strand conformation analysis. The region upstream to the coding sequence we investigated contains two functional promoters. Screening 42 patients with bipolar affective disorder, we detected 11 DNA sequence variants (48T/A, 267 + 275C/T, 805T/G, 1777C/A, 1827C/T, 1904C/T, 2126G/T, 2294insT, 2776C/T, 2777del36, 2819T/G). Determining the frequency of these variants in 42 anonymous blood donors, we observed a non-significant (P < 0.06) trend towards an underrepresentation of the 2126T variant in patients when compared to controls. On the other hand, the 2777del36 and the 2819G variant were not found among the controls. These findings were followed up in a large independent replication sample. However, we were not able to confirm the initial findings in the second sample. Our data suggest that genetically determined variation of the A1AR and its two promoters do not play a major role in the development of bipolar affective disorder. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 81:18–23, 1998. © 1998 Wiley-Liss, Inc.

Adenosine A1 receptor and bipolar affective disorder: systematic screening of the gene and association studies.

Human adenosine A1 receptor gene: systematic screening for DNA sequence variation and linkage mapping on chromosome 1q31-32.1 using a silent polymorphism in the coding region.

Jürgen Deckert

Papers

Human adenosine A2a receptor (A2aAR) gene: systematic mutation screening in patients with schizophrenia

Neuronal nicotinic acetylcholine receptor α4 subunit (CHRNA4) and panic disorder: An association study

Adenosine A1 receptor and bipolar affective disorder: systematic screening of the gene and association studies.

Human adenosine A1 receptor gene: systematic screening for DNA sequence variation and linkage mapping on chromosome 1q31-32.1 using a silent polymorphism in the coding region.