Extracellular cAMP: The Past and Visiting the Future in cAMP‐Enriched Extracellular Vesicles

Abstract

It is recently discovered that the cyclic nucleotide, cyclic adenosine monophosphate (cAMP) can be enriched in the extracellular vesicles (EVs) isolated from endothelial cells. In the current perspective a historical context for the discovery of the extracellular cAMP is provided. The story of extracellular cAMP through investigations addressing the molecule's role in the adenosine pathway is followed, which is widespread in mammalian physiology. The adenosine pathway mediates normal physiological conditions such as renin release, phosphate transport, etc., and participates in pathological conditions such as bronchoconstriction of the airways. Furthermore, adenosine mediated biological pathways are regulated via the receptor mediated intracellular cAMP pathway in mammalian cells. It then speculates on the question of whether cAMP enriched EVs could bypass typical receptor mediated cell signaling and directly activate cAMP signaling cascade in target cells. Preliminary studies to suggest cAMP enriched EVs are provided, added to naïve endothelial cells, results in an increase in intracellular cAMP. An alternate mechanism is proposed, apart from the traditional adenosine pathway, that extracellular cAMP may exert its effects and put into perspective how it might consider circulating cAMP moving forward.

Comparative Genomics of Thaumarchaeota From Deep-Sea Sponges Reveal Their Niche Adaptation

“…The regulation of intracellular concentration of cAMP is dependent not only on the synthesis of cAMP but also on the hydrolysis of cAMP by cAMP phosphodiesterase ( Imamura et al, 1996 ). In low glucose conditions, cAMP can act as an intracellular signaling molecule that allows bacteria to adapt to this changing environment and use a secondary source of carbon such as lactose, such process is known as catabolite repression ( Bhadra et al, 2021 ). Low glucose conditions could activate adenylyl cyclase which increases the cAMP concentration, and through a series of processes, relevant enzymes and transport proteins were expressed for the usage of available carbon sources ( Ullmann and Monod, 1968 ; Rickemberg, 1974 ; De Crombrugghe et al, 1984 ).…”

Adenine, a key player in biology and medicinal chemistry

“…cAMP is a versatile chemical second messenger that mediates extracellular signals to intracellular responses in most types of cells. Many biological processes are regulated by cAMP such as cell activation, proliferation, migration or apoptosis regulation [122]. The cAMP response is first initiated by primary signaling molecules (hormones, neurotransmitters or prostaglandins) that activate mainly G-Protein-Coupled Receptors (GPCR), which in turn activate adenylyl cyclases (Figure 7A).…”

“…EPACs activate Ras-like small GTPases (Rap1 and Rap2) that are involved in cell-cell adhesion [122,125,130]. EPAC1 and EPAC2 have been identified as potent targets for several human diseases, as in cancer and cardiovascular diseases, thus small molecules modulating EPAC have been developed.…”