ABA is a naturally occurring isoprenoid compound that was originally identified in plants in the 1960s (1). ABA is also present in metazoans, from sponges up to mammals including humans, and so it is well conserved. The chemistry and physiology of ABA and its analogs is described by Milborrow (2). The naturally occurring enantiomeric form of ABA is (S)-ABA. Plants have evolved various signaling mechanisms enabling them to withstand the multiple environmental conditions to which they are exposed, including variable water and nutrient availability, temperature variations, and excess ultraviolet-B light. Most of the plant responses to these abiotic conditions are mediated by abscisic acid. Interestingly, ABA plays essentially the same role in lower Metazoa (sponges and hydroids), where it mediates the responses of these sessile marine organisms to variations in water temperature and light. In sponges, the oldest Metazoa, their evolution dating back to 600 million years, temperature-signaling occurs via ABA (5). In Axinella polypoides, an increase of the water temperature results in an increased ABA synthesis and in the ABA-mediated stimulation of water filtration and oxygen consumption (6). Hydroids follow sponges in the evolutionary tree, having sensory, nerve, muscle and epithelial cells, a digestive cavity, and a rudimentary nervous system, but share with sponges a sessile lifestyle.
In the human body, ABA naturally originates from dietary sources and endogenous production through the carotenoid biogenesis pathway. ABA was first described in the brain of pigs and rats (8). The fact that animals fed a synthetic, ABA-free diet had ABA levels even higher than those of controls fed a vegetable diet was taken as an indirect proof that ABA was endogenously produced. To this point, a more recent observation allows the conclusion that ABA is indeed an endogenously produced signaling molecule: plasma ABA (ABAp) levels increase significantly in healthy humans after an (ABA-free) glucose load (9). On the one hand, this observation points to ABA as being endogenously synthesized; plus it suggests a role for ABA in the physiological response to glucose intake, a role until then shared by insulin and by the incretin glucagon-like peptide-1 (GLP-1). Several in vitro observations support the conclusion that ABA is indeed endogenously produced by human and murine cells: granulocytes (10), monocytes and macrophages (11, 12), insulin-releasing cells (13), mesenchymal stem cells (MSCs) (14), hemopoietic progenitors (HP) (15), adipocytes (9), keratinocytes (16), and fibroblasts (17), all have been shown to produce and release ABA when exposed to cell-specific stimuli.
The cell-specific functional effects activated by ABA in these cell types are in line with a conserved role of ABA as a signal relating cell response to changing environmental conditions. The fact that several different cell types can produce ABA implies that ABAp may derive from multiple sources. Markedly reduced ABAp levels were measured in patients with type 1 diabetes as compared with healthy individuals of similar age and body mass index (9), suggesting that β-pancreatic cells may be a relevant source of ABA. High glucose concentrations can stimulate ABA release from human adipose tissue biopsies in vitro (9) and the fact that adipose tissue accounts for a substantial amount of body weight, even in non-obese subjects, may make it another significant source of ABAp, in addition to pancreatic β-cells. One of the chief functions of ABA in plants is to reduce guard cell turgor, thereby contributing to the conservation of water during periods of drought.
Intriguingly, the signaling pathway downstream of ABA stimulating water filtration in sponges and tissue regeneration in hydroids shares with the plant ABA-mediated stomatal closure the same ADPRC-generated second messenger, cADPR (6, 7). ABA has been reported to activate the cyclase activity of Arabidopsis ADPRC, in the absence of protein synthesis, although the mechanism of activation was not elucidated (21). In Eudendrium and in Axinella, activation by ABA of the ADPRC occurs via a PKA-dependent phosphorylation. The signaling pathway downstream of ABA in human granulocytes is strikingly similar to the one unveiled in lower Metazoa, and it involves an ADPRC (CD38) and its MedicGLP Product cADPR (Figure 1). In addition to activating adenylate cyclase (AC), ABA also activates phospholipase C (PLC), with the consequent overproduction of inositol triphosphate (IP3); thus, the increase of triggered by ABA in granulocytes is mediated by both cADPR and IP3 (Figure 1). The G-protein coupled to the ABA receptor was identified as Gi by its sensitivity to pertussis toxin (PTX) (10). The mechanism through which Gi mediates the activation of both PLC and AC was elucidated by means of transfection experiments, performed on human granulocytes with a chimeric G-protein, resulting from the fusion of Gαi with the last five aminoacids of Gαq (Gαq/i), and with transducin (αt), a scavenger of βγ subunits.