Adenosine Receptor Reserve and Long-Term Potentiation: Unconventional Adaptive Mechanisms in Cardiovascular Diseases?

Abstract

While the concept of a receptor reserve (spare receptors) is old, their presence on human cells as an adaptive mechanism in cardiovascular disease is a new suggestion. The presence of spare receptors is suspected when the activation of a weak fraction of receptors leads to maximal biological effects, in other words, when the half-maximal effective concentration (EC50) for a biological effect (cAMP production, for example) is lower than the affinity (KD) of the ligand for a receptor. Adenosine is an ATP derivative that strongly impacts the cardiovascular system via its four membrane receptors, named A1R, A2AR, A2BR, and A3R, with the A1R being more particularly involved in heart rhythm, while the A2AR controls vasodilation. After a general description of the tools necessary to explore the presence of spare receptors, this review focuses on the consequences of the presence of spare adenosine receptors in cardiovascular physiopathology. Finally, the role of the adenosinergic system in the long-term potentiation and its possible consequences on the physiopathology are also mentioned.

A Body of Circumstantial Evidence for the Irreversible Ectonucleotidase Inhibitory Action of FSCPX, an Agent Known as a Selective Irreversible A1 Adenosine Receptor Antagonist So Far

“…These observations underline the importance of research efforts aiming an understanding of heart physiology and pathophysiology, with special emphasis on interspecies differences. An important topic in this field is the investigation of endogenous cardioprotective mechanisms such as the cardiac adenosinergic system [ 3 , 4 , 5 , 6 ], a system in which species dependence is also present [ 7 ]. Of course, in the usual sequence of information acquisition in life sciences, animal experiments will precede human studies for a long time to come.…”

“…Accordingly, adenosine is a substrate for several enzymes and transporters [8,9]. CHA (N 6 -cyclohexyladenosine) and CPA (N 6 -cyclopentyladenosine) are synthetic adenosine analogues that act as selective, biologically stable (enzyme-resistant, especially CHA [10]) and high-efficacy (especially CPA [11]) full agonists for the A 1 adenosine receptor (A 1 receptor). The A 1 receptor is the predominant adenosine receptor type of the myocardium that mediates several protective processes including negative tropic effects (primarily on the supraventricular myocardium) [8,12,13].…”

Adenosine, Adenosine Receptors and Neurohumoral Syncope: From Molecular Basis to Personalized Treatment

“…Interestingly, the presence of spare receptors in this population was associated with a low adenosine plasma concentration level and mainly with negative HUT [40]. Yet, it was postulated that the presence of spare receptors could be an adaptive mechanism to low agonist concentration levels, low receptor production levels or both [42,43].…”

“…This last dimension is named K D (affinity constant), while the concentration of agonists necessary to obtain half of the maximal biological effects is named EC 50 . Thus, from a practice point of view, the presence of receptor reserves is evidenced by a high K D /EC 50 ratio [42,43]. Specific tools are necessary to evaluate the presence of spare receptors.…”

Co-inhibition of adenosine 2b receptor and programmed death-ligand 1 promotes the recruitment and cytotoxicity of natural killer cells in oral squamous cell carcinoma

“…Moreover, under A2BR deficiency, a mouse ischemic heart model showed an increased number of immune cells, including B cells, NK cells, and CD4 T-cells. Additionally, A2BR plays an important role in the proliferation, differentiation, and apoptosis of cancer cells ( Guieu et al, 2021 ; Augustin et al, 2022 ). Generation of purine nucleosides in TME effectively inhibits T-cell and NK cell activities, studies have found that A2AR and A3R play critical roles in tumor immune responses ( Zahavi & Hodge, 2023 ; Strickland et al., 2023 ).…”