A single second messenger: several possible cellular responses depending on distinct subcellular pools.

Multiple Enzyme Isoforms Provide the Cell With Tools to Precisely Control Second Messenger Levels Second messengers are defined as small molecules that are synthesized in the cell in response to extracellular first messengers,1 and diffuse through the cytoplasm to mediate their effects. This definition is sometimes broadened to include hydrophobic molecules, such as diacylglycerol (DAG).2 Synthesis and degradation of second messengers are regulated by a number of enzymes expressed in mammalian cells. Such enzymes include, but are not limited to, adenylyl cyclase (AC) for synthesis of cyclic AMP (cAMP), guanylyl cyclase for synthesis of cyclic GMP (cGMP), cyclic nucleotide phosphodiesterase (PDE) for hydrolysis of cAMP and cGMP, and phospholipase C (PLC) for hydrolysis of phosphatidylinositol 4,5-bisphosphate to inositol 1,4,5trisphosphate (IP3) and DAG. Each of these enzyme groups consists of a plethora of isoforms. Thus, there are 10 different gene products in the mammalian AC gene family (AC1–9 and an atypical soluble AC isoform).3–5 Furthermore, different splice variants of AC4, AC5, and AC8 have been cloned.6–8 A large number of PDE and PLC isoforms have also been cloned. To date, 21 different PDE genes divided among 11 gene families have been identified in mammals.9 Most PDE families consist of more than 1 gene products, and most genes code for more than 1 messenger RNA. Although some PDE gene families hydrolyze cAMP exclusively (PDE4, PDE7, and PDE8), many of these enzymes hydrolyze both cAMP and cGMP (PDE1, PDE2, PDE3, PDE10, and PDE11), and some hydrolyze cGMP exclusively (PDE5, PDE6, and PDE9).9 There are at least 13 different PLC isoforms generating IP3 and DAG, which also exist in several different splice variants.10–11 Thus, the number of enzyme isoforms regulating synthesis and degradation of any given second messenger, even within 1 cell, is almost mind-boggling, and raises the question: Why are there so many different isoforms of enzymes catalyzing the synthesis or degradation of the same second messenger? It is generally believed that the large number of second messenger-synthesizing and -degrading enzyme isoforms provide the cell with tools to precisely regulate second messenger levels in different subcellular compartments and following exposure to different stimuli.