Molecular biological approaches to unravel adenylyl cyclase signaling and function

Signal transduction through the cell membrane requires the participation of one or more plasma membrane proteins. For many transmembrane signaling eve nts adenylyl cyclases (ACs) are the final effector enzymes which integrate and interpret divergent signals from different pathways. The enzymatic acti vity of adenylyl cyclases is stimulated or inhibited in response to the act ivation of a large number of receptors in virtually all cells of the human body. To date, ten different mammalian isoforms of adenylyl cyclase (AC) ha ve been cloned and characterized. Each isoform has its own distinct tissue distribution and regulatory properties, providing possibilities for differe nt cells to respond diversely to similar stimuli, The product of the enzyma tic reaction catalyzed by ACs, cyclic AMP (cAMP) has been shown to play a c rucial role for a variety of fundamental physiological cell functions rangi ng from cell growth and differentiation, to transcriptional regulation and apoptosis, In the past, investigations into the regulatory mechanisms of AC s were limited by difficulties associated with their purification and the a vailability of the proteins in any significant amount. Moreover, nearly eve ry cell expresses several AC isoforms. Therefore, it was difficult to perfo rm biochemical characterization of the different AC isoforms and nearly imp ossible to assess the physiological roles of the individual isoforms in int act cells, tissue or organisms. Recently, however, different molecular biol ogical approaches have permitted several breakthroughs in the study of ACs. Recombinant technologies have allowed biochemical analysis of adenylyl cyc lases in-vitro and the development of transgenic animals as well as knock-o ut mice have yielded new insights in the physiological role of some AC isof orms. In this review, we will focus mainly on the most novel approaches and concepts, which have delineated the mechanisms regulating AC and unravelle d novel functions for this enzyme. (C) 2001 Elsevier Science B.V. All right s reserved.