PDE 2013, Paris, France: Another Exciting Workshop for Cyclic AMP, Protein Kinase A, and Phosphodiesterases

This special issue of Hormone and Metabolic Research includes the proceedings of the 3^rd international workshop (PDE 2013) on cyclic AMP (cAMP)/protein kinase A (PKA) signaling and phosphodiesterases (PDEs). The meeting took place at Hospital Cochin, in Paris, France ([Fig. 1]), and followed the previous 2 workshops that were held in Bethesda, MD [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11]. It also followed our long time commitment in studying endocrine tumors and their link to the cAMP/PKA pathway and PDEs, as demonstrated by our reports and meetings published in this journal [12] [13] [14] [15].

Fig. 1 The participants at the PDE 2013 workshop pose for a picture in the grounds of the historic cloister of the Hospital Cochin, Paris, France in July 11–12, 2013 (colour figure available online only).

The workshop focused on the genetics of the molecules participating in this pathway and their association with human diseases; the PDE meetings have served for more than 6 years now as the main international forum bringing together clinicians, structural and molecular biologists, geneticists, and pharmacologists who are interested in the cAMP/PKA/PDE signaling pathway.

The ubiquitous cAMP-signaling pathway plays a major role in physiology and disease. Despite the fact that cAMP was described as a second messenger more than 55 years ago, only recently the technology allowed us to understand how this omnipresent signaling pathway mediates so many diverse signals in such a specific manner. The development of imaging methods at the cellular and molecular levels, the availability of various omics approaches [16], and the advances in structural biology and human molecular genetics especially with regards to cAMP/PKA and PDEs [17] were essential steps in elucidating many issues surrounding the transmission of the signal and its localizing and tissue-, cell- and time-specific effect.

The contents of this special issue highlight some of these developments, which were discussed during the workshop and represent the state-of-the-art in the cAMP/PKA/PDE field.

Calebiro et al. [18] show how fluorescence resonance energy transfer technology allows the real-time monitoring of GPCR signaling to unravel the dynamics of cAMP regulation by the TSH receptor. Compartimentalization is clearly now a new important layer of the fine tuning of the cAMP signal at the cellular level. Rogne and Tasken [19] illustrate this important process in the physiology of the adipocyte. The cAMP signaling pathway is indeed an important regulator of the fat tissue and metabolism. Weinstein [20] shows that the central nervous system plays also a role in this control by the study of glucose metabolism in mouse models with inactivated Gs alpha. How cAMP/PKA control cell survival and the effects of drugs that are used to treat pituitary tumors are presented by Insel et al. [21] and by Peverelli et al. [22].

The third workshop on cAMP/PKA signaling and PDEs had also a special emphasis on adrenal tumors. Indeed among human tumors, adrenocortical lesions that are responsible for cortisol excess are associated with alterations of many of the genes of the pathway including 2 PDEs (PDE8B and PDE11A). The review by Szarek and Stratakis [23] describes these associations. More recently, several groups have reported activating mutations of the gene of the catalytic subunit of PKA (PRKACA) in cortisol-secreting adrenal adenomas; these data are reviewed by Espiard et al. [24]. In a specific form of bilateral adrenal tumor (macronodular adrenal hyperplasia) causing cortisol excess, Louiset et al. [25] present how abnormal expression of membrane receptors that signal trough cAMP/PKA can be shown. Basso et al. [26] show the important role of the regulatory subunits R1A and R2B of PKA in the adrenocortical cell cycle. In tumors of the adrenal cortex, other important genes recently discovered that might indirectly alter cAMP signaling, such as ARMC5, are presented by Berthon and Stratakis [27]. Finally, to come back to the important role of cAMP/PKA and PDEs in the regulation of adiposity and metabolism, London et al. [28] demonstrate how obesity differs among patients with various types of Cushing syndrome depending on the molecular cause of cortisol excess.

In summary, this special issue illustrates very well how much we have learned and to what extent we understand the functions of a key signaling pathway, that involving cAMP, PKA and the PDEs. It also points to the many unresolved questions that involve various fields of medicine, from endocrinology and metabolism to cardiology and urology. If these genes are ubiquitous and highly polymorphic, why only a few diseases are known to be associated with them? And despite the length of time that pharmacology has had in exploiting the PDEs and the cAMP signaling pathway, the issue of specificity of the developed drugs, from those used on asthma to those treating erectile dysfunction, still dogs the field. Hence, this exciting field has a bright future and we are looking forward to the upcoming workshops.

• References

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