The biology of the A BR is complex

The biology of the A2BR is complex and needs to be considered contextually as the expression and effect of receptor engagement varies according to time post hypoxic injury, cell type and downstream signaling pathway. For example, A2BR expression is dynamic - low under basal and increasing under ischemic conditions. In the case of kidney ischemia, upregulation of A2BR occurs early and remains elevated for 4 weeks after injury. The A2BR possesses two downstream signaling pathways. It is intriguing that the effect of A2BR engagement differs in acute and chronic ischemic induced kidney disease. Whereas acute activation of the A2BR protects in models of renal IRI, chronic activation promotes renal fibrosis. It may be that preferential signaling pathways differ according to cell type and clinical setting. For example, Wilkinson et al. demonstrated that the A2BR is expressed on renal fibroblasts and activation increases cAMP via Gs signaling promoting renal fibrosis. This is in keeping with our published data which showed an increase in A2BR expression in parallel with renal fibrosis and that sustained elevated adenosine levels exaggerated the fibrotic response. Interestingly Du et al. have shown that A2BR activation on human microvascular endothelial HG-9-91-01 increases vascular endothelial growth factor (VEGF) production via cAMP and endothelial NO Synthase (eNOS) upregulation via phosphatidylinositol-phospholipase C pathway. Furthermore, in a model of hind limb ischemia eNOS was shown to be critical for repair. Finally, Moriyama and Sitkovsky showed that the A2AR promoted the cell surface expression of the A2BR concluding that these receptors form a hetero-oligomeric complex for better function. Indeed recent evidence suggests that the G-protein coupled receptor superfamily as a whole may signal as monomers, hetero- and homodimers (reviewed in 7). Thus our data which suggest that AMP may play a role in acute renal IRI via activation of the A2BR and preferential downstream Gq signaling adds yet another layer of complexity to purinergic signaling specifically in the context of renal IRI.
Introduction Human dental pulp cells (HDPCs) have attracted the interest of researchers in the field of tissue regeneration because of their accessibility and abundance of stem/progenitor cells [1,2]. Recent studies have reported that HDPCs can differentiate not only into odontoblasts for dentin regeneration, but also into osteoblasts, which can repair bone defects under appropriate conditions [3,4]. The differentiation of mesenchymal cells in HDPCs into odontoblasts is induced by multiple cytokines such as four and a half LIM domains 2 (FHL2) [5], bone morphogenetic protein (BMP2) [6], and ID1 (a downstream target of BMP2 signaling) [7]. Purinergic signaling can regulate the proliferation [8], differentiation [9], and death [8] of different types of stem cells. As critical signaling molecules in this pathway, adenosine triphosphate (ATP) and its hydrolysates act through purinergic receptors, which are classified into P1 (adenosine receptors [ARs], e.g. A1R, A2AR, A2BR, and A3R) and P2 (P2XR, e.g. P2X1–7R; P2YR, e.g. P2Y1,2,4,6,11–14R) receptors. P1 receptors are primarily activated by adenosine, whereas those in the P2 category are mainly regulated by purines such as ATP and adenosine diphosphate (ADP) [10]. Cutarelli et al. [11] were the first to report the biphasic effects of ATP on differentiation and mineralization in human osteoblasts, showing an increase in these processes in response to low concentrations (<100 μM), whereas high concentrations (>100 μM) led to a decrease in these processes, which they suggested was due to the combined activation of P2 receptors and ATP hydrolysis products (e.g. ADP, AMP, adenosine, the mineralization inhibitor PPi, and the mineralization promoter inorganic phosphate [Pi]). In contrast, the osteogenic effects of ATP on human bone marrow mesenchymal stem cells was due to adenosine stimulation of the AR subtype, A2BR [12].