Phosphodiesterases and cyclic nucleotide signaling in endocrine cells.

The discovery of cyclic nucleotides as second messengers has paved the way to much of what we know about signal transduction and the mechanisms of hormone action. Even though other signaling pathways activated by growth factors are the focus of much attention, cyclic nucleotides remain among the most important players in hormone action. When envisioned as a linear cascade, the steps involved in cyclic nucleotide signaling are well defined. Hormones bind to receptors that are coupled via G proteins to cyclases, which synthesize cAMP/cGMP. Cyclic nucleotides, in turn, bind and activate protein kinases that phosphorylate enzymes and transcription factors. Changes in gene expression and cell metabolism are the final outcome. This reductionist approach has been most effective in elucidating the steps involved in cyclic nucleotide signaling as well as the downstream targets. However, we must realize that several major questions have remained unanswered. Why does an identical cAMP signal induce replication in one case and withdrawal from the cell cycle and differentiation in another? How do the myriad of feedback regulations, which are being discovered at a steady pace, impact cyclic nucleotide signaling? How does one explain the redundancy of the components of the cyclic nucleotide cascade? Over the years, new dimensions have added complexity to cyclic nucleotide signaling. It is now established that protein kinase As (PKAs) are not the only intracellular effectors of cAMP. Cyclic nucleotide gated channels (1) and cAMP-regulated guanine nucleotide exchange factors (cAMP-GEFs or EPACs) (2, 3) allow branching of the cyclic nucleotide signals. Compartmentalization of the different components of the signaling cascade is an important determinant of the signal outcome (4), and feedback mechanisms control practically every step of the cyclic nucleotide pathway (5). Therefore, a holistic approach to signaling may provide a better understanding of how cyclic nucleotides function in the cell. Signaling pathways, including cyclic nucleotides, are organized in a nonlinear fashion (6). When an extracellular stimulus reaches the plasma membrane, it is distributed into an array of signals that involves most transduction systems present in a cell, and each component of the signaling cascade is a node of inputs and outputs connecting different signaling pathways. Combinatorial signaling, coincidental detection, signal cross-talk, and signal channeling are buzzwords used to describe this intracellular network. In this context, some steps in the signaling cascade may have new and unexpected functions. In the cyclic nucleotide cascade, phosphodiesterases (PDEs) are the enzymes that hydrolyze cAMP and cGMP, inactivating these second messengers. Together with phosphatases, PDEs are negative steps in the signaling pathway, and signal termination was thought to be their only function. However, they may have a much broader role in signaling when the whole intracellular network is considered. In view of the presence of multiple intracellular effectors of cyclic nucleotides, PDEs may play a role in distributing the cyclic nucleotide signal among PKAs, cyclic nucleotidegated channels, and cAMP-GEFs. Because they are regulated by multiple second messengers and kinases, PDEs also integrate the cyclic nucleotide cascade with other signaling pathways. Finally, PDEs may contribute to signal compartmentalization by controlling the diffusion of the second messenger to different cellular compartments. Here, I will review the most recent advances concerning the structure of PDEs and their role in endocrine cell signaling, and will conclude by highlighting possible applications of the pharma0888-8809/00/$3.00/0 Molecular Endocrinology 14(9): 1317–1327 Copyright © 2000 by The Endocrine Society Printed in U.S.A.