Different phosphodiesterases (PDEs) regulate distinct phosphoproteomes during cAMP signaling.

Sixty years ago, Sutherland and Rall identified cAMP as the first second messenger involved in cell–cell communication (reviewed in ref. 1). For many years, Sutherland had been interested in understanding how hormones, such as catecholamines, released by one cell type could alter the characteristics of a target cell because hormones of this type were charged, and therefore could not enter the cell. Sutherland termed compounds, such as hormones and neurotransmitters, released by one cell type that were capable of altering the properties of target cells in cell–cell communication, as “first messengers.” He reasoned that these first messengers, upon binding to the external surface of the target cell, might stimulate the synthesis of a “secondmessenger” on the inner surface of the target cell’s membrane, which would travel into the target cell’s interior and redirect the machinery of that cell (Fig. 1). With the discovery of cAMP, Sutherland and Rall proved this theory and thus the field of signal transduction was born. Ten years later it was discovered that the actions of cAMP resulted from its binding to and activating effector proteins, termed cAMPdependent protein kinases, or PKAs (reviewed in ref. 1). PKAs are serine/threonine kinases that phosphorylate a wide range of protein substrates, almost all of which contain the consensus amino acid sequence R-R/K-X-S/T-Y, where X represents any small amino acid and Y represents a large hydrophobic amino acid. Phosphorylation of a target enzyme by PKA can lead to either activation or inhibition of enzymatic activity, depending on the particular target enzyme. In addition to this posttranslational modification of enzymatic activities, cAMP can regulate the transcriptional expression of a wide range of proteins through the PKA phosphorylation and regulation of transcription factors (Fig. 1). Thirty years after the discovery of PKA as an effector of cAMP, another cAMP effector, exchange protein activated by cAMP (EPAC), was discovered as a Rap1 guanine-nucleotide exchange factor directly activated by cAMP (2), and a third class of effectors, cyclic nucleotide-gated channels (CNGC), was also found to exist (3). Several reports have provided evidence for actions of cAMP independent of these three effectors, suggesting that additional effectors of cAMP action may yet be uncovered (Fig. 1) (reviewed in ref. 4). The level of cAMP within cells is controlled by its rate of synthesis from ATP by adenylyl cyclases (ACs), its rate of degradation to 5′-AMP by cyclic nucleotide phosphodiesterases (PDEs), and to some extent by extrusion out of the cell (Fig. 1) (5, 6). In the late 1970s, Brunton, Hayes, and Mayer observed a differential effect of two agonists of adenylyl cyclase, isoproterenol (ISO) and prostaglandin E1 (PGE1), on cardiac myocytes. Whereas both agonists increased cAMP levels, and both activated a soluble fraction of PKA, only ISO Fig. 1. Role of PDEs in regulation of signal transduction. In themodel of the secondmessenger concept originally put forth by Sutherland and Rall (14), first messengers—such as hormones, neurotransmitters, cytokines, and growth factors—upon interacting with receptors on the cell surface, generate the production of a second messenger, such as cAMP, which then redirects the machinery of the cell, affecting many physiological processes. PDEs, by controlling the steady-state levels and temporal and spatial components of cAMP, are central to controlling and regulating this signal transduction. ATF-1, activating transcription factor-1; CREB, cAMP-response element binding protein; CREM, cAMP-response element modulator; Gs, stimulatory guanine nucleotide-binding protein; ICER, inducible cAMP early repressor protein; R, G protein-coupled metabotropic receptor. Reproduced with permission from ref. 4.