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In-Depth Information
Table 7.1
Characterization of adenosine receptor subtypes. Adenosine receptors are character-
ized into four subtypes based on its affinity towards adenosine and coupling to G-proteins, which
activate or inhibit adenylyl cyclase
Adenosine
receptors
Effect on adenyly
cyclase activity
Effect on cAMP
production
Affinity for
adenosine
References
A1
Inhibitory
Decreases
High
(
[15, 52]
10
−
8
M)
∼
A2A
Stimulatory
Increases
High
(
[15, 52]
10
−
7
M)
∼
A2B
Stimulatory
Increases
Low
(
[8]
10
−
5
M)
∼
A3
Inhibitory
Decreases
Low
(
[15]
10
−
5
M)
∼
adenylyl cyclase and are Gi (inhibitory G-protein)-coupled, the A
2A
and A
2B
recep-
tors are Gs (stimulatory G protein)-coupled (Table 7.1). Both the high affinity A
2A
and the low affinity A
2B
receptors activate adenylyl cyclase, resulting in increases
in intracellular cAMP. Among the adenosine receptors, both adenosine A
2A
and
the related A
2B
receptors have unique properties, and are distinctly regulated in
endothelial as well as other cell types. The activated adenosine A
2A
receptor exhibits
anti-inflammatory properties [54] and can protect against tissue injury in a number
of organ systems [10, 42, 46, 55, 59, 62]. On the other hand adenosine A
2B
receptor
can exhibit both pro- and anti-inflammatory properties depending on the cell type
[11, 19, 34, 53].
HIFs also regulate expression of adenosine receptors A
2A
and A
2B
in endothelial
cells (Fig. 7.1). Endothelial cells can express either A
2A
receptor or A
2B
recep-
tor or both [25, 56]. Adenosine A
2B
receptor expression is regulated by HIF-1
α
in microvascular endothelial cells of the dermis [40]. By contrast, A
2B
receptor
expression was shown to be unresponsive to hypoxia and HIFs in microvascular
endothelial cells derived from the pulmonary circulation [3]. In addition, adeno-
sine A
2A
receptor expression can be regulated by HIF-2
in these
lung microvascular cells. It is interesting that adenosine receptors are regulated
so differently even in microvascular endothelial cells of different tissue origins.
This indicates fundamental differences in growth regulation of the microvasculature
in the pulmonary versus the systemic circulation, similar to differences in micro-
versus macrovessels [38]. Adenosine A
2A
receptor also promotes proliferation of
lung microvascular endothelial cells upon its activation [3, 45]. This is in contrast
to studies in other cell types, including PC12 (pheochromocytoma) and smooth
muscle cells, where activation of adenosine A
2A
receptor caused decreased prolif-
eration [45, 67, 69]. Similarly other studies with PC12 cells showed that there was
a decrease in cell viability upon activation of the receptor in one investigation [73],
whereas inhibition of apoptosis was observed in another [36]. Taken together, these
studies point to a differential regulation and function of the receptor in cells and tis-
sues. These studies show that either adenosine A
2A
receptor or the related adenosine
α
but not HIF-1
α
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