Ai receptors

Adenosine is produced by many tissues, mainly as a byproduct of ATP breakdown. It is released from neurons, glia and other cells, possibly through the operation of the membrane transport system. Its rate of production varies with the functional state of the tissue and it may play a role as an autocrine or paracrine mediator (e.g. controlling blood flow). The uptake of adenosine is blocked by dipyridamole, which has vasodilatory effects. The effects of adenosine are mediated by a group of G protein-coupled receptors (the Gi/o-coupled Ai- and A3 receptors, and the Gs-coupled A2a-/A2B receptors). Ai receptors can mediate vasoconstriction, block of cardiac atrioventricular conduction and reduction of force of contraction, bronchoconstriction, and inhibition of neurotransmitter release. A2 receptors mediate vasodilatation and are involved in the stimulation of nociceptive afferent neurons. A3 receptors mediate the release of mediators from mast cells. Methylxanthines (e.g. caffeine) function as antagonists of Ai and A2 receptors. Adenosine itself is used to terminate supraventricular tachycardia by intravenous bolus injection. 

Presently, only adenosine itself is approved for clinical use. It is used widely in the treatment of supraventricular tachycardia and in cardiac stress imaging to assess coronary artery disease [5]. Other agonists and antagonists and an allosteric modulator of the Ai receptor are in clinical trials for a variety of indications. 

Binding and mRNA measurements show A2A receptors on the GABA/ENK neurons with D2 receptors and Ai receptors on the GABA/SP neurons which express mainly Dj receptors (Fig. 15.9). The A2A receptors have been most studied. 

There are important inhibitory systems built into the control of events following C-fibre stimulation. Thus, during peripheral noxious stimulation, spinal mechanism, driven by NMDA-receptor-mediated activity, can become active to damp down further neuronal responses, the purine, adenosine (see Chapter 13), appears to be involved in this type of control and has been reported to be effective in humans with neuropathic pain. It is thought that the depolarisations caused by activation of the NMDA receptor increase the metabolic demand on neurons and so ATP utilisation increases. ATP then is metabolised to adenosene and the purine then acts on its inhibitory Ai receptor in the... 

Figure 7 Displacement of 0.4 nM [3H] DPCPX by various concentrations of CPA from human wild-type (CHO A,) and mutant (CHO A1-mutT277A) adenosine Ai receptors in the absence ( ) or presence ( ) of PD81,723 (10 pM).

Bruns RF, Fergus JH. Allosteric enhancement of adenosine Ai receptor binding and function by 2-amino-3-benzoylthiophenes. Mol Pharmacol 1990 38 939-949. 

Mathot RAA, van der Wenden EM, Soudijn W, Ijzerman AP, Danhof M. Deoxyribose analogues of A -cyclopcnty I adenosine (CPA) are partial agonist at the adenosine Ai receptor in vivo. Br J Pharmacol 1995 116 1957-1964. 

Musser B, Mudumbl RV, Liu J, Olson RD, Vestal RE. Adenosine Ai receptor-dependent and -independent effects of the allosteric enhancer PD 81,723. J Pharmacol Exp Ther 1999 288 446 454. 

Dalpiaz A, Townsend-Nicholson A, Beukers MW, Schofield P, Ijzerman AP. Thermodynamics of full agonist, partial agonist and antagonist binding to wild type and mutant adenosine Ai receptors. Biochem Pharmacol 1998 56 1437-1445. 

Noradrenaline acts on three types of receptor. The ai receptors mediate the main excitatory effects of noradrenaline upon wake-active neurons in the dorsal raphe, basal forebrain, and elsewhere (Vandermaelen Aghajanian, 1983 Nicoll, 1988 Fort et al., 1995 Brown et al., 2002). The a2 receptors mediate inhibitory effects of noradrenaline, e.g. on noradrenaline neurons themselves and on cholinergic brainstem neurons (Williams et al., 1985 Williams Reiner, 1993). The (3-receptors modulate neurons in a more subtle fashion, increasing excitability via blockade of afterhyperpolarizations in hippocampal and cortical neurons (Haas Konnerth, 1983). Activation of (3-receptors also promotes synaptic plasticity via activation of the cyclic-AMP-dependent kinase (PKA) and cyclic AMP response element binding protein (CREB) signal transduction pathway (Stanton Sarvey, 1987 Cirelli et al., 1996). 

Infusion of prostaglandin D2 (200 pmol/min) or the adenosine A2a receptor agonist CGS21680 (20 pmol/min) for 2 h into the subarachnoid space under the BF, during the dark period, increased NREM sleep and reduced c-Fos protein in the TMN of rats when compared with saline-treated controls (Scammell et al., 1998, 2001). In contrast, infusion of the adenosine Ai receptor agonist N6-cyclopentyl-adenosine (2 pmol/min) in the same area did not have any effect on sleep-wakefulness or c-fos expression in the TMN. 

Adenosine has been proposed to induce sleep by inhibiting cholinergic neurons of the BFB and the brainstem. In this respect, adenosine and the adenosine transport inhibitor NBTI decrease the discharge rate of BFB neurons during W, whereas the adenosine Ai receptor antagonist CPDX induces the opposite effects (Alam et al., 1999 Strecker et al., 2000). In addition, perfusion of adenosine into... 

Monti, J. M., Jantos, H. Monti, D. (2001). Increase of waking and reduction of NREM and REM sleep after nitric oxide synthase inhibition prevention with GABAa or adenosine Ai receptor agonists. Behav. Brain Res. 123, 23-35. 

Neural mechanisms of the hypnogenic effect of adenosine the case for an Ai-receptor-mediated action in the BF... 

The experiment in Figure 13-3 illustrates the use of flow cytometry to determine Kj and B ax values for binding of the es nucleoside transporter ligand, SAENTA-fiuorescein, at sites in human CEM leukemic lymphoblasts. The es nucleoside transporter is widely expressed in mammalian cells, and is concentrated in regions in the CNS that coordinately express adenosine Ai receptors (Jennings et al., 2001). 

The a.1 receptors are excitatory in their action, while the a2 receptors are inhibitory, these activities being related to the different types of second messengers or ion channels to which they are linked. Thus, a2 receptors hyperpolarize presynaptic membranes by opening potassium ion channels, and thereby reduce noradrenaline release. Conversely, stimulation of ai receptors increases intracellular calcium via the phosphatidyl inositol cycle which causes the release of calcium from its intracellular stores protein kinase C activity is increased as a result of the free calcium, which then brings about further changes in the membrane activity. 

Smooth muscle effects. The opposing effects on smooth muscle (A) of a-and p-adrenoceptor activation are due to differences in signal transduction (p. 66). This is exemplified by vascular smooth muscle (A). ai-Receptor stimulation leads to intracellular release of Ca + via activation of the inositol tris-phosphate (IP3) pathway. In concert with the protein calmodulin, Ca + can activate myosin kinase, leading to a rise in tonus via phosphorylation of the contractile protein myosin. cAMP inhibits activation of myosin kinase. Via the former effector pathway, stimulation of a-receptors results in vasoconstriction via the latter, P2-receptors mediate vasodilation, particularly in skeletal muscle - an effect that has little therapeutic use. 

Methyldopa (dopa = dihydroxy-phenylalanine), as an amino acid, is transported across the blood-brain barrier, decarboxylated in the brain to a-methyldopamine, and then hydroxylat-ed to a-methyl-NE The decarboxylation of methyldopa competes for a portion of the available enzymatic activity, so that the rate of conversion of L-dopa to NE (via dopamine) is decreased. The false transmitter a-methyl-NE can be stored however, unlike the endogenous mediator, it has a higher affinity for a2- than for ai-receptors and therefore produces effects similar to those of clonidine. The same events take place in peripheral adrenergic neurons. 

Changes in adrenergic function are complex. Inhibition of neuronal catecholamine reuptake gives rise to superimposed indirect sympathomimetic stimulation. Patients are supersensitive to catecholamines (e.g., epinephrine in local anesthetic injections must be avoided). On the other hand, blockade of ai-receptors may lead to orthostatic hypotension. 

Long-Term Effects of ai-Receptor Deletion on the Cardiovascular System... 

The anticonvulsant activity of diazepam, assessed by its protection against pentylenetetrazole-induced tonic convulsions, was strongly reduced in ai-(HIOIR) mice compared to wild-type animals (Rudolph et al. 1999). Sodium phenobarbital remained fully effective as anticonvulsant in ai(HlOlR) mice. Thus, the anticonvulsant activity of benzodiazepines is partially but not fuUy mediated by ai receptors. The anticonvulsant action of zolpidem is exclusively mediated by ai receptors, since its anticonvulsant action is completely absent in ai(HlOlR) mice (Crestani et al. 2000). 

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