Cannabigerol (CBG) is one of the major phytocannabinoids present in Cannabis sativa L. that is attracting pharmacological interest because it is non-psychotropic and is abundant in some industrial hemp varieties. The aim of this work was to investigate in parallel the binding properties of CBG to cannabinoid CB₁ (CB₁R) and CB₂ (CB₂R) receptors and the effects of the compound on agonist activation of those receptors and of CB₁–CB₂ heteroreceptor complexes. Using [³H]-CP-55940, CBG competed with low micromolar K_i values the binding to CB₁R and CB₂R. Homogeneous binding in living cells, which is only technically possible for the CB₂R, provided a 152 nM K_i value. Also interesting, CBG competed the binding of [³H]-WIN-55,212-2 to CB₂R but not to CB₁R (K_i: 2.7 versus >30 μM). The phytocannabinoid modulated signaling mediated by receptors and receptor heteromers even at low concentrations of 0.1–1 μM. cAMP, pERK, β-arrestin recruitment and label-free assays in HEK-293T cells expressing the receptors and treated with endocannabinoids or selective agonists proved that CBG is a partial agonist of CB₂R. The action on cells expressing heteromers was similar to that obtained in cells expressing the CB₂R. The effect of CBG on CB₁R was measurable but the underlying molecular mechanisms remain uncertain. The results indicate that CBG is indeed effective as regulator of endocannabinoid signaling.

(1) Background. N-methyl d-aspartate (NMDA) ionotropic glutamate receptor (NMDAR), which is one of the main targets to combat Alzheimer’s disease (AD), is expressed in both neurons and glial cells. The aim of this paper was to assess whether the adenosine A_2A receptor (A_2AR), which is a target in neurodegeneration, may affect NMDAR functionality. (2) Methods. Immuno-histo/cytochemical, biophysical, biochemical and signaling assays were performed in a heterologous cell expression system and in primary cultures of neurons and microglia (resting and activated) from control and the APP_Sw,Ind transgenic mice. (3) Results. On the one hand, NMDA and A_2A receptors were able to physically interact forming complexes, mainly in microglia. Furthermore, the amount of complexes was markedly enhanced in activated microglia. On the other hand, the interaction resulted in a novel functional entity that displayed a cross-antagonism, that could be useful to prevent the exacerbation of NMDAR function by using A_2AR antagonists. Interestingly, the amount of complexes was markedly higher in the hippocampal cells from the APP_Sw,Ind than from the control mice. In neurons, the number of complexes was lesser, probably due to NMDAR not interacting with the A_2AR. However, the activation of the A_2AR receptors resulted in higher NMDAR functionality in neurons, probably by indirect mechanisms. (4) Conclusions. A_2AR antagonists such as istradefylline, which is already approved for Parkinson’s disease (Nouriast^® in Japan and Nourianz^® in the US), have potential to afford neuroprotection in AD in a synergistic-like fashion. i.e., via both neurons and microglia.

Extracellular adenosine accumulates in the environment of numerous tumors. For years, this fact has fueled preclinical research to determine whether adenosine receptors (ARs) could be the target to fight cancer. The four ARs discovered so far, A₁, A_2A, A_2B and A₃, belong to the class A family of G protein-coupled receptors (GPCRs) and all four have been involved in one way or another in regulating tumor progression. Prompted by the successful anti-cancer immunotherapy, the focus was placed on the ARs more involved in regulation of immune cell differentiation and activation and that are able to establish molecular and functional interactions. This review focuses on the potential of A_2A and A_2B receptor antagonists in cancer control and in boosting anti-cancer chemotherapy and immunotherapy. The article also overviews the ongoing clinical trials in which A_2AR and A_2BR ligands are being tested in anti-cancer therapy.

ACE2 plays a pivotal role in the balance between the pro-oxidative pro-inflammatory and the anti-oxidative anti-inflammatory arms of the renin-angiotensin system. Furthermore, ACE2 is the entry receptor for SARS-CoV-2. Clarification of ACE2-related mechanisms is crucial for the understanding of COVID-19 and other oxidative stress and inflammation-related processes. In rat and monkey brain, we discovered that the intracellular ACE2 and its products Ang 1–7 and alamandine are highly concentrated in the mitochondria and bind to a new mitochondrial Mas-related receptor MrgE (MrgE) to produce nitric oxide. We found MrgE expressed in neurons and glia of rodents and primates in the substantia nigra and different brain regions. In the mitochondria, ACE2 and MrgE expressions decreased and NOX4 increased with aging. This new ACE2/MrgE/NO axis may play a major role in mitochondrial regulation of oxidative stress in neurons, and possibly other cells. Therefore, dysregulation of the mitochondrial ACE2/MrgE/NO axis may play a major role in neurodegenerative processes of dopaminergic neurons, where mitochondrial dysfunction and oxidative stress play a crucial role. Since ACE2 binds SARS-CoV-2 spike protein, the mitochondrial ACE2/MrgE/NO axis may also play a role in SARS-CoV-2 cellular effects.