Adenosine is a purine nucleoside present in all human cells where it plays many different
physiological roles: From being a building block for nucleic acids to a key constituent
of the biological energy currency ATP [1]. Indeed, more than 90 years ago, Drury and
Szent-Györgyi reported that adenosine produces profound hypotension and bradycardia
[2], and until the present time, the list of physiological effects of adenosine has
expanded considerably [3]. In addition, adenosine is a well-known neuromodulator in
the brain and has effects on other tissues, thus exerting its physiological actions
through four different subtypes of G protein-coupled adenosine receptors (i.e., A1R,
A2AR, A2BR and A3R) which, as expected, are expressed in a large variety of cells
throughout the body [4]. Consequently, ARs are potential therapeutic targets in a
variety of pathophysiological conditions, including cancer, cardiovascular diseases,
neurological disorders, and inflammatory and autoimmune diseases [5].
Consequently, the interest in the molecular structure and pharmacology of ARs has
increased in recent years. Interestingly, more than 30 crystal structures for human
ARs have been reported in the last decade, thus, they are the most structurally characterized
G protein-coupled receptor at the molecular level. In addition, selective agonists
and antagonists for all four AR subtypes have been developed and their diagnostic
and therapeutic utility is being pursued.
The following special issue of the International Journal of Molecular Sciences aims
at providing the recent developments in ARs from several points of view, thus going
from mechanistic aspects of ligand-receptor interaction to physiopathological features
involving adenosine receptors. Accordingly, four review articles highlight the relevance
of AR targeting in some pathologies and the pharmacotherapeutic usefulness of targeting
these receptors. Fenouillet et al. review the concept of “receptor reserve”, also
known as “spare receptors”, in the field of adenosinergic transmission and its implication
in cardiovascular disorders [6]. Interestingly, AR reserve allows adenosine to achieve
its maximal efficacy without the need of occupying all cell ARs. As indicated by the
authors [6], spare ARs within the cardiovascular system appear to compensate for a
low extracellular adenosine level and/or a low adenosine receptor number, such as
in coronary artery disease (CAD) [7] or some kinds of neurocardiogenic syncope [8].
Thus, the existence of spare receptors appears to be an attempt to overcome a weak
interaction between adenosine and its receptors. Finally, the authors hypothesize
that the identification of adenosine spare receptors in cardiovascular disorders may
be helpful for diagnostic purposes. Next, Wolska and Rozalski further review the current
knowledge of using synthetic, selective, longer-lasting agonists for A2AR and A2BR
on platelet function inhibition, thus assessing their potential use for anti-platelet
pharmacotherapy [9]. Hence, the authors highlight the renewed interest in using A2AR
agonists as anti-platelet therapy in the management of arterial thrombosis, a disorder
that often results in cardiovascular disease and stroke. Interestingly, the combination
in a multimodal fashion of A2AR agonists (i.e., NECA, HE-NECA, CGS 21680, 2-chloroadenosine
and PSB-15826) with other purinergic-based anti-platelet agents, for instance P2Y12
receptor antagonist (i.e., cangrelor, clopidogrel or prasugrel), may represent a promising
approach to prevent thrombotic events [9]. Gao and Jacobson discuss the role of A2BR
in cancer [10]. Interestingly, while all four ARs are reported to be somehow involved
in cancer progression [11], A2BR signaling constitutes a major pathway contributing
to cancer cell proliferation and solid tumor growth, angiogenesis and metastasis,
as the authors listed [10]. Thus, A2BR antagonists are potentially a novel anticancer
therapy, either in combination with other anticancer drugs or as a monotherapy. Indeed,
several A2BR antagonists (i.e., AB928 26, PBF-1129 and theophylline 11) are now in
clinical trials for patients with various types of cancers. Finally, Golay et al.
performed a systematized survey and analysis of the literature to review the current
status of animal and human research on G protein-coupled receptors (GPCRs) in the
context of selected hematopoietic stem cell transplantation (HSCT) outcomes [12].
Interestingly, A2AR activation limits graft-versus-host disease after allogenic hematopoietic
stem cell transplantation [13] and mediates an increase in donor-derived regulatory
T cell suppression development of graft-versus-host disease [14].
Subsequently, nine research articles assess new functional, mechanistic, medicinal
chemistry and pathophysiological prospects for ARs. Thus, Szabo et al. implemented
the receptorial responsiveness method (RRM) to estimate the known concentrations of
stable synthetic A1R agonists in isolated, paced guinea pig left atria [15]. Interestingly,
the RRM is a procedure that is based on a simple nonlinear regression while using
a model with two variables (X, Y) and (at least) one parameter to be determined (cx)
[16]. Mocking et al. developed a bioluminescence resonance energy transfer (BRET)-based
G protein-activation assay to probe duration of GPCR blockade [17]. Interestingly,
the assay monitors heterotrimeric G protein activation via scavenging of released
Venus-Gβ1γ2 by NanoLuc (Nluc)-tagged membrane-associated-C-terminal fragment of G
protein-coupled receptor kinase 3 (masGRK3ct-Nluc) as a tool to probe duration of
GPCR antagonism [17]. Next, Pelassa et al. provide biochemical (i.e., co-immunoprecipitation)
and biophysical (i.e., proximity ligation assay) evidence confirming that endogenous
A2AR and dopamine D2 receptor (i.e., D2R) heteromerize at the plasma membrane of rat
striatal astrocytes [18]. Since striatal astrocytes are recognized to be involved
in Parkinson’s disease (PD) pathophysiology, the findings reported here shed light
on the molecular mechanisms involved in the pathogenesis of the disease. Borroto-Escuela
et al. present further evidence that A2AR-D2R heteromers in the nucleus accumbens,
through A2AR mediated allosteric inhibition of the D2R, can increase anti-reward in
the ventral striatopallidal GABA neurons and inhibit cocaine self-administration,
whereas the A2AR homodimer does not appear to be involved in this allosteric mechanism
[19]. Subsequently, Fernández-Dueñas et al. describe the development of a new AlphaScreen
assay to detect GPCR oligomers in post-mortem human brains, thus confirming for the
first time the existence of A2AR/D2R heteromers in human caudate [20]. In brief, antibodies
against A2AR and D2R were selectively labelled with donor and acceptor beads to engage
in a singlet oxygen energy transfer, dependent on the formation of A2AR/D2R heteromers.
Importantly, by using this approach, the authors show that the A2AR/D2R heteromerization
status may be increased in the caudate from PD patients. Thus, restoring the unbalanced
A2AR/D2R heteromer function potentially associated with PD may help to better understand
the disease etiology and to design selective combined pharmacotherapeutic strategies
[20]. Then, Okada et al. demonstrate that both acute and chronic administrations of
therapeutic-relevant concentrations of carbamazepine (CBZ)—an anticonvulsive drug
that also binds to adenosine receptors—suppress excitatory astroglial glutamatergic
transmission associated with IP3-R and AMPA-R [21]. Importantly, the A2AR agonistic
action of CBZ contributes to chronic mechanisms of carbamazepine against several neuropsychiatric
disorders via inhibition of astroglial pathomechanisms of proinflammatory responses
of IFNγ and TNFα [21]. Irrera et al. investigate the efficacy of polydeoxyribonucleotide
(PDRN), a biologic A2AR agonist, in an experimental model of psoriasis-like dermatitis
[22]. Indeed, PDRN decreased pro-inflammatory cytokines, prompted Wnt signaling, reduced
IL-2 and increased IL-10. Thus, the authors concluded that PDRN anti-psoriasis potential
may be linked to a “dual mode” of action: (i) NF-κB inhibition, and ii) Wnt/β-catenin
stimulation [22]. Finally, Hayashi assesses the molecular and functional expression
of adenosine receptors in the exocrine pancreases of rats, mice, and guinea pigs [23].
Interestingly, the author concludes that A2AR is a net contributor to exocrine secretion
in the rodent pancreas, an assumption based on: (i) A2AR agonists stimulating a HCO3
−-rich fluid secretion, and (ii) A2AR colocalizing with ezrin in the luminal membrane
of duct cells [23]. Lertsuwan et al. propose a novel adenosine-mediated cancer cell
growth and invasion suppression via a receptor-independent mechanism in cholangiocarcinoma
(CCA) [24]. Indeed, the authors postulated a novel adenosine-mediated cancer cell
suppression through a receptor-independent but nucleoside-transporter-dependent mechanism
in CCA cells, thus extracellular adenosine treatment led to increased intracellular
adenosine, which was later phosphorylated to 5′ AMP by adenosine kinase with the concomitant
activation of 5′ AMP-activated protein kinase (AMPK) [24].
Overall, we hope that this timely focused issue summarizing our current knowledge
on adenosine receptors will be of interest to a wide range of readers of the journal,
interested in the purinergic field. Finally, we wish to express our best thanks to
all authors and co-authors of the issue for their commitment and to the anonymous
reviewers for their excellent contributions.