Message delivered: how myocytes control cAMP signaling.

See related article, pages 1091–1100 Despite the vast array of specific receptors and ligands through which cells receive information from their outside environment, the first line of messengers that relay this onto internal signaling cascades is more limited. Yet, somehow, the purpose of the original message is conveyed (ie, we know who knocked on the front door), and the message ends up influencing just the right proteins to produce the desired effect. A striking example of this selectivity is the cyclic nucleotides for which only 2 basic types exist; cAMP and cGMP. Despite this limited cast, these molecules precisely regulate many complex and disparate cellular activities. Their trick is to be in the right place at the right time and with the right amount of signal. It is now well established that cyclic nucleotides are spatially compartmentalized to enable different external triggers to vary the internal cellular response.1–5 This can be achieved by localizing the cyclases that synthesize cAMP or cGMP in different parts of the cell, parking the effector kinase protein kinase (PK)A in particular regions by means of anchoring proteins (AKAPs)6 (may apply to PKG though still unclear), and targeting phosphodiesterases to one area or another and/or providing them with hierarchical control.1 The latter is thought to be particularly important by limiting diffusion of a cyclic nucleotide from its site of generation to other parts of the cell. There are eleven 3′,5′-phosphodiesterase (PDE) subfamily members with approximately 50 isoforms, targeting cAMP, cGMP, or in some instances both.7 Given that many of these PDEs can themselves be activated by cyclic nucleotides and/or their effector kinases, the system has substantial built-in complexity for localized regulation. Compartmental signaling was first …