Physiology and effects of nucleosides in mice lacking all four adenosine receptors

Abstract

Adenosine is a constituent of many molecules of life; increased free extracellular adenosine indicates cell damage or metabolic stress. The importance of adenosine signaling in basal physiology, as opposed to adaptive responses to danger/damage situations, is unclear. We generated mice lacking all four adenosine receptors (ARs), Adora1−/−;Adora2a−/−;Adora2b−/−;Adora3−/− (quad knockout [QKO]), to enable investigation of the AR dependence of physiologic processes, focusing on body temperature. The QKO mice demonstrate that ARs are not required for growth, metabolism, breeding, and body temperature regulation (diurnal variation, response to stress, and torpor). However, the mice showed decreased survival starting at about 15 weeks of age. While adenosine agonists cause profound hypothermia via each AR, adenosine did not cause hypothermia (or bradycardia or hypotension) in QKO mice, indicating that AR-independent signals do not contribute to adenosine-induced hypothermia. The hypothermia elicited by adenosine kinase inhibition (with A134974), inosine, or uridine also required ARs, as each was abolished in the QKO mice. The proposed mechanism for uridine-induced hypothermia is inhibition of adenosine transport by uridine, increasing local extracellular adenosine levels. In contrast, adenosine 5′-monophosphate (AMP)–induced hypothermia was attenuated in QKO mice, demonstrating roles for both AR-dependent and AR-independent mechanisms in this process. The physiology of the QKO mice appears to be the sum of the individual knockout mice, without clear evidence for synergy, indicating that the actions of the four ARs are generally complementary. The phenotype of the QKO mice suggests that, while extracellular adenosine is a signal of stress, damage, and/or danger, it is less important for baseline regulation of body temperature.

Bone Marrow and Adipose Tissue Adenosine Receptors Effect on Osteogenesis and Adipogenesis

“…Interestingly, using the PET radioligand, [ 11 C]TMSX, which binds specifically to the A2aAR, lean men were found to have reduced brown adipose tissue radioligand binding (a marker of A2aAR receptor density) following cold exposure [ 84 ]. However, in mice lacking all four ARs, termed quadruple knockout mice (QKO), body temperature did not differ from WT mice [ 85 ], suggesting that ARs are not necessary for baseline body temperature or that the four adenosine receptors may have reciprocal and opposing effects on body temperature such that deletion of one adenosine receptor is balanced by the deletion of a different adenosine receptor. Regardless, the role of the A2aAR in brown adipose tissue appears to be clinically relevant and may lead to future therapeutic efforts.…”

Copper Toxicity Links to Pathogenesis of Alzheimer’s Disease and Therapeutics Approaches

“…It is present in all cells containing glia and neurons, initiates its biological process by four G-protein coupled receptors (GPCRs), namely, the A1, A2A,…A2BAR [ 43 , 44 ]. It has a role in regulating and integrating neuronal excitability, affecting many essential brain activities like sleep, memory, and neural plasticity [ 45 , 46 , 47 ]. Much research has analyzed adenosine effects via its receptors A1 and A2A in AD [ 48 ].…”

Adenosine-Related Mechanisms in Non-Adenosine Receptor Drugs

“…The four AR subtypes (A 1 , A 2A , A 2B , and A 3 ; Figure 1) are important in the body's adaptation to stress [1,3], often in the context of increasing local blood flow by vasodilation. However, a knockout (KO) mouse line lacking all four ARs displayed no differences in growth, fertility, metabolism, and thermal regulation, although long-term survival was diminished [2]. This suggested that ARs have a more pronounced role to regulate allostasis, i.e., to restore the stability of an organism in response to challenges or stresses, than homeostasis, which maintains unperturbed physiological parameters.…”

“…Drugs can affect adenosine signaling in multiple ways. They can act directly as ligands for one or more of the four G protein-coupled receptors (GPCRs) for adenosine [1][2][3]. Alternatively, they can stimulate or inhibit pathways of adenosine generation, degradation, or clearance [4][5][6][7].…”