Molecular characterization

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Despite the fact that adenosine receptors were well characterized and partially purified, the two first adenosine receptors cloned, A1 and A2a, came from a library of orphan receptors from the dog thyroid (Maenhaut etal. 1990; Libert etal. 1991). Soon the same receptors were cloned from rat and humans (Mahan etal. 1991; Furlong etal. 1992), and a related receptor, the A2b receptor, was cloned from rat brain (Stehle et al. 1992). Whereas these receptors had all been predicted from extensive pharmacological studies, the fourth receptor, A3 was more unexpected (Zhou et al. 1992). These four adenosine receptors have now been cloned from a variety of mammalian and non-mammalian species (Table 11.1). A1, A2a, and A2b receptors are well conserved among mammals, whereas A3 receptors show considerable structural variability.

For all four adenosine receptors the coding region is split up by an intron in a region corresponding to the second intracellular loop (Fredholm et al. 2000). When the structure of the A1 receptor was first reported the presence of two major transcripts were noted. The

Table 11.1 Adenosine receptors

Adenosine A1

Adenosine A2A

Adenosine A2B

Adenosine A3

Alternative names

Ri; A1R

A2a, Rs; A2AR

A2b, Rs; A2BR

A3R

Structural information (Accession no.)

h 326 aa (P30542) r 326 aa (P25099) m 326 aa (Q60612)

h 410 aa (P29274) r 409 aa (P30543) m 409 aa (UO5672)

h 328 aa (P29275) r 332 aa (P29276) m 332 aa (UO5673)

h 318 aa (P33765) r 320 aa (P28647) m 320 aa (AF069778)

Chromosomal location

1q32.1

22q11.2

I7pl1.2—12

1p13.3

Selective agonists

CPA, CCPA, CHA

CGS21680, HE-NECA, CV1808, CV1674, ATL146e

Cl-IB-MECA

8-cyclopentyltheophylline, WRC0571

SCH 58261, (moderately selective) ZM241385, KF17387, CSC

MRS1754, enprofylline, alloxazine

MRS1220, MRE3008-F20, MRS1191, MRS1523

Radioligands

[3H]-DPCPX, [3H]-CHA

[3H]-CGS21680, [3H]-SCH58261, [3H]-ZM241385

([3H]-ZM241385, [3H]-DPCPX)

[3H]-MRE3008-F20

G protein coupling

Gi/Go

Gs/Golf

Gs/Gq

Gi/Go

Expression profile

brain including cerebral cortex, cerebellum, hippocampus, dorsal horn of spinal cord, eye, adrenal gland

striatopallidal GABAergic neurons, caudate-putamen, nucleus accumbens, tuberculum olfactorium, olfactory bulb, low in other brain regions

blood vessels, eye, median eminence, mast cells, low levels in adrenal and pituitary glands

brain but particularly cerebellum, hippocampus

Physiological function

bradycardia, inhibition of lipolysis, reduced glomerular filtration, tubulo-glomerular feedback, antinociception, reduction of sympathetic and parasympathetic activity, presynaptic inhibition, neuronal hyperpolarization, ischemic preconditioning

regulation of sensorimotor integration in basal ganglia, inhibition of platelet aggregation and polymorphonuclear leukocytes, vasodilatation, protection against ischemic damage, stimulation of sensory nerve activity

relaxation of smooth muscle in vasculature and intestine, inhibition of monocyte and macrophage function, stimulation of mast cell mediator release (some species)

enhancement of mediator release from mast cells (some species), preconditioning (some species)

Knockout phenotype

anxiety, hyperalgesia, decreased tolerance to hypoxia, loss of tubulo-glomerular feedback

anxiety, hypoalgesia, hypertension, increased tolerance to ischemia, altered sensitivity to motor stimulant drugs, decreased platelet aggregation

altered inflammatory reactions, altered release of inflammatory mediators, decreased edema

Disease relevance

acute and chronic pain, renal failure, sleep disorders, epilepsy, obesity, brain and cardiac ischemia

Parkinson's disease, schizophrenia, asthma, inflammation

asthma, inflammation

asthma, inflammation, cardiac ischemia

functional consequences of this have since been elucidated (Ren and Stiles 1994, 1995). Transcripts containing exons 4, 5, and 6 were found in all tissues expressing the receptor, whereas transcripts containing exons 3, 5, and 6 were in addition found in tissues such as brain, testis, and kidney that express high levels of the receptor. There are two promoters, a proximal one denoted promoter A, and a distal one denoted promoter B, which are about 600 bp apart. The A2a receptor shows one hybridizing transcript in most tissues examined (Maenhaut et al. 1990; Stehle et al. 1992). It should also be mentioned that the human adenosine A2a receptor is polymorphic. In particular, a (silent) T1083C mutation occurs in various populations, more frequently in Caucasians than in Asians (Deckert et al. 1996). The rat A2b receptor shows two hybridizing transcripts of 1.8 and 2.2 kb, where the latter is predominant (Stehle etal. 1992). This could, in analogy with the above, suggest the presence of multiple promoters. The human A3 receptor shows two transcripts: the most abundant being approximately 2 kb in size, and the less abundant about 5 kb (Atkinson et al. 1997), perhaps indicating similarities with the A1 receptor gene.

The four adenosine receptor subtypes are asparagine-linked glycoproteins and all but the A2a have sites for palmitoylation near the carboxyl terminus (Linden 2001). Depalmitoyla-tion of A3 (but not A1) receptors renders them susceptible to phosphorylation by G protein-coupled receptor kinases (GRKs), which in turn results in rapid phosphorylation and desensitization (Palmer and Stiles 2000).

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