Adenosine subtypes

Exposure of any GPCR to its agonist for shorter or longer times generally leads to an attenuation of the agonist response (Krupnick and Benovic 1998 Lefkowitz 1998 Pitcher et al. 1998 Ferguson 2001). Adenosine receptor are no exception (Olah and Stiles 2000) however, the magnitude of the response and the mechanism involved seem to be different for the four adenosine subtypes. 

In conclusion as for the role of A3 receptors in the inhibition of TNF-a production in macrophages discrepant results have been obtained and not only due to the different species considered. For example some studies attributed reduction of TNF-a to A3 receptors either in human and mouse species (Sajjadi et al. 1996 McWhinney et al. 1996), whilst other found this effect to be mediated essentially by A2A and in minor part by A2B without the involvement of the A3 receptors again in both human and mouse species (Zhang et al. 2005 Kreckler et al. 2006). Therefore it is difficult in this case to verify the relevance of the A3 receptor-induced cellular response when other adenosine subtypes like A2A and A2B are also activated. As for the effects exerted by the A3 subtype in human monocytes and macrophages it is possible to find support for an anti-inflammatory role for this receptor as attested by reduction of tissue factor, oxidative burst and perhaps TNF-a release. Also the recent discovery of an increase in MMP9 supports a role for A3 agonists in the therapy of myocardial infarction (Velot et al. 2008) (Fig. 12.4). 

The relevance of the A3 receptor over the other adenosine subtypes in immature human dendritic cells is attested to by different studies demonstrating a role for this receptor in the increase of intracellular calcium, actin polymerization and chemot-axis (Panther et al. 2001 Fossetta et al. 2003) (Fig. 12.5). However a loss of the A3 and an increase of the A2A receptor has been reported during maturation of dendritic cells. This switch has been interpreted as a protective effect of adenosine in the context of tissue injury as A2A activation plays an inhibitory role on dendritic cells migration. In this way adenosine could counterbalance inflammatory stimuli by delaying the arrival of mature dendritic cells to lymph nodes, thereby impairing the... 

Adenosine receptors are members of the P purinoceptor GPCR family and can be classified into four subtypes A, 3 ... 

Unlike classical neurotransmitters, adenosine does not have a rapid synaptic uptake system (as for the biogenic amines), and its chemical inactivation system is not as rapid as for the transmitter acetylcholine, for example. Adenosine may be metabolized extracellularly and inactivated with respect to the ARs in a more general fashion by the widespread enzymes adenosine kinase (AK, to produce AMP) and adenosine deaminase (AD, to produce inosine). Both AMP and inosine are only weakly active at ARs, depending on the subtype. 

Adenosine Receptors. Table 1 Characteristics of the four subtypes of adenosine receptors (human, unless noted)... 

Adenosine Receptors. Table 2 Affinity of commonly used adenosine receptor agonists and antagonists for defining pharmacologically adenosine receptor subtypes... 

Adenosine Receptors. Figure 3 An alignment of the primary sequences of the four human AR subtypes. Regions of conservation are highlighted. indicates the most conserved (X.50) residue in each TM region. Bold residues correspond to those indicated in Table 1. The A2A receptor is truncated in the carboxy-terminal region. 

PI (adenosine) receptors were explored as therapeutic targets before P2 receptors. Adenosine was identified early and is in current use to treat supraventricular tachycardia. A2a receptor antagonists are being investigated for the treatment of Parkinson s disease and patents have been lodged for the application of PI receptor subtype agonists and antagonists for myocardial ischaemia and reperfusion injury, cerebral ischaemia, stroke, intermittent claudication and renal insufficiency. 

Serotoninergic System. Figure 1 Graphical representation of the current classification of 5-hydroxytryptamine (5-HT) receptors. Receptor subtypes represented by shaded boxes and lowercase designate receptors that have not been demonstrated to definitively function in native systems. Abbreviations 3-5r cyclic adenosine monophosphate (cAMP) phospholipase C (PLC) negative (-ve) positive (+ve)... 

Stiles GL. Adenosine receptor subtypes new insights from cloning and functional studies. In Jacobson KA, Jarvis MF, eds. Purinergic Approaches in Experimental Therapeutics. New York Wiley-Liss, 1997 29-37. 

Rivkees SA, Lasbury ME, Barbahalya H. Identification of domains of the human Ai adenosine receptor that are important for binding receptor subtype selective ligands using chimeric Ai/A2 adenosine receptors. J Biol Chem 1995 270 20485-20490. 

Marks, G. A., Shaffery, J. P., Speciale, S. G. Birabil, C. G. (2003). Enhancement of rapid eye movement sleep in the rat by actions at Al and A2A adenosine receptor subtypes with a differential sensitivity to atropine. Neuroscience 116, 913-20. 

Sinciair, C. J., et al. Nucleoside transporter subtype expression effects on potency of adenosine kinase inhibitors. Br. J. Pharmacol. 2001, 134, 1037-1044. 

The P-site of adenylyl cyclase inhibits cyclic AMP accumulation 308 There are four adenosine receptor subtypes 308 Xanthines block P2 but not P2 receptors 309... 

There are four adenosine receptor subtypes. There are four subtypes of adenosine (Pj) receptor that have... 

TABLE 17-2 Subtypes of adenosine receptor, their effectors and selective agonists and antagonists ... 

A1 adenosine receptors are inhibitory in the central nervous system. A receptors were originally characterized on the basis of their ability to inhibit adenylyl cyclase in adipose tissue. A number of other G-protein-mediated effectors of A receptors have subsequently been discovered these include activation of K+ channels, extensively characterized in striatal neurons [13], and inhibition of Ca2+ channels, extensively characterized in dorsal root ganglion cells [14]. Activation of A receptors has been shown to produce a species-dependent stimulation or inhibition of the phosphatidylinositol pathway in cerebral cortex. In other tissues, activation of A receptors results in synergistic activation of the phosphatidylinositol pathway in concert with Ca2+-mobilizing hormones or neurotransmitters [15]. The effectors of A adenosine receptors and other purinergic receptor subtypes are summarized in Table 17-2. 

These effects of ATP are blocked by pertussis toxin, and so the putative ATP receptor is G-protein linked. ATP addition results in phospholipase C activation, which may be detected as increased inositol phosphate metabolism and subsequent elevations in cytosolic free Ca2+. Purinergic receptors on many types of cells are classified as type Pi or P2. Neutrophils possess P2-type receptors, which are activated by ATP and ADP, and also Pi-type receptors, which are activated by adenosine. Occupancy of P2-type receptors enhances fMet-Leu-Phe-mediated effects, whilst occupancy of Pi-type receptors has the opposing effect. Some pharmacological evidence suggests that the P2-type receptor on neutrophils is distinct from the P2X and P2y subtypes that have been described in other cell types. 

Several indirect neurochemical effects of methyixanthines contribute to their effects. Micromolar concentrations of caffeine enhance release of acetylcholine (Pedata et al. 1984). However, this effect is biphasic, augmenting release at 50 pM, but decreasing it at 0.5 pM. This effect is also modulatory, affecting stimulated, but not basal, release. Caffeine enhances acetylcholine release in the hippocampus, which is due to adenosine Al receptor subtypes (Carter et al. 1995). Conversely, chronic caffeine reduces the excitatory effect of acetylcholine in the cerebral cortex (Lin and Phillis... 

Okada M, Kawata Y, Murakami T, Wada K, Mizuno K, Kondo T, Kaneko S. (1999). Differential effects of adenosine receptor subtypes on release and reuptake of hippocampal serotonin. EurJ Neurosci. 11(1) 1-9. 

To date, five subtypes of these receptors have been cloned. However, initial studies relied on the pharmacological effects of the muscarinic antagonist pirenzepine which was shown to block the effect of several muscarinic agonists. These receptors were termed Mi receptors to distinguish them from those receptors for which pirenzepine had only a low affinity and therefore failed to block the pharmacological response. These were termed M2 receptors. More recently, M3, M4 and M5 receptors have been identified which, like the Mi and M2 receptors occur in the brain. Recent studies have shown that Mi and M3 are located posts)maptically in the brain whereas the M2 and M4 receptors occur pres)maptically where they act as inhibitory autoreceptors that inhibit the release of acetylcholine. The M2 and M4 receptors are coupled to the inhibitory Gi protein which reduces the formation of cyclic adenosine monophosphate (cyclic AMP) within the neuron. By contrast, the Mi, M3 and M5 receptors are coupled to the stimulatory Gs protein which stimulates the intracellular hydrolysis of the phosphoinositide messenger within the neuron (see Figure 2.8). 

Five subtypes of dopamine receptors have been described they are the Dj-like and Dj-like receptor groups. All have seven transmembrane domains and are G protein-coupled. The Dj-receptor increases cyclic adenosine monophosphate (cAMP) formation by stimulation of dopamine-sensitive adenylyl cyclase it is located mainly in the putamen, nucleus accumbens, and olfactory tubercle. The other member of this family is the D5-receptor, which also increases cAMP but has a 10-fold greater affinity for dopamine and is found primarily in limbic regions. The therapeutic potency of antipsychotic drugs does not correlate with their affinity for binding to the Dj-receptor. 

The postsynaptic S-adrenoceptors (jS-ARs) belong to the rhodopsin/ S2 adrenergic receptor-like receptors that belong to one of three major subfamilies of the GPCRs [83]. The S-AR family is subdivided into at least three discrete subtypes, the ySr, )S2-AR [84], and the atypical jSa-AR [85,86]. Additionally, a putative subtype has been identified in cardiac tissue, classified as the P4-AR [87], The P-]- and S2-AR are Gs-protein coupled, thereby elevating the intracellular level of cyclic adenosine monophosphate (cAMP) and causing positive inotropic and chronotropic effects [88]. The P2-AR can also couple to the Grprotein. 

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