Compartmentalization of cyclic nucleotide signaling: a question of when, where, and why?

Abstract

Preciseness of cellular behavior depends upon how an extracellular cue mobilizes a correct orchestra of cellular messengers and effector proteins spatially and temporally. This concept, termed compartmentalization of cellular signaling, is now known to form the molecular basis of many aspects of cellular behavior in health and disease. The cyclic nucleotides cyclic adenosine monophosphate and cyclic guanosine monophosphate are ubiquitous cellular messengers that can be compartmentalized in three ways: first, by their physical containment; second, by formation of multiple protein signaling complexes; and third, by their selective depletion. Compartmentalized cyclic nucleotide signaling is a very prevalent response among all cell types. In order to understand how it becomes relevant to cellular behavior, it is important to know how it is executed in cells to regulate physiological responses and, also, how its execution or dysregulation can lead to a pathophysiological condition, which forms the scope of the presented review.

Figure 1

An activated G protein coupled receptor (GPCR) triggers cAMP synthesis from membrane-bound adenylyl cyclase (AC) and subsequently, a cAMP-regulated microdomain is constituted in which a cAMP-responsive target (here CFTR) gets instantaneously regulated by controlled flux of cAMP reflected by a precise balance of synthesis by AC, extrusion by cAMP-efflux transporters (here MRP4) and catabolism by phosphodiesterases (PDEs). Formation of a macromolecular complex assembled onto specialized scaffolds that communicate with the cytoskeletal elements can be a theme of the cyclic-nucleotide microdomain. MRP4 and cGMP-specific PDE can also regulate the flow of cGMP synthesized by guanylate cyclase (GC) in the vicinity of cGMP-responsive proteins. Indicates activated GPCR. cAMP cGMP