Adenylyl Cyclase and cAMP as Second Messenger

The adenylyl cyclases catalyze the formation of 3 -5 -cyclic AMP (cAMP) from ATP (Fig. 5.25). cAMP is a widespread signal molecule that primarily functions via activation of protein kinases (see Section 6.1 and Chapter 7). Synthesis of cAMP by adenylyl cyclase is opposed by degradation and inactivation by phosphodiesterases. 

Despite the central importance of adenylyl cyclase for hormonal signal transduction, its structural and functional characterization is incomplete. In mammals, at least 9 different membrane-bound types of adenylyl cyclase are described these are known as adenylyl cyclases of types I - IX and show a high degree of sequence homology (ca. 50%) (review Tesmer and Sprang, 1998 Patel et al., 2001). In addition, one cytosolic adenylyl cyclase has been described to date. 

The adenylyl cyclases are large transmembrane proteins with a complex transmembrane topology. The assumed topology (Fig. 5.26) shows a short cytoplasmic N-term-inal section followed by a transmembrane domain Ml with six transmembrane sections, and a large cytoplasmic domain Cl. The structural motif is repeated so that a second transmembrane domain M2 and a second cytoplasmic domain C2 can be differentiated. 

Information on the structure-function relationship of adenylyl cyclase is available, in particular for the cytoplasmic domain. According to this, the important functions of 

Interestingly, adenylyl cyclase V also influences the activation of various G proteins by the activated receptor (Scholich et al., 1999). It facilitates the onset of signaling by agonist-bound receptors so that the amount of receptor required to activate the enzyme is drastically reduced. This function may serve to amplify signaling in the presence of low concentrations of ligand or receptor. The mechanistic basis of this influence remains to be elucidated. An apparent paradox arises in which the same protein inactivates Ga s and facilitates activation of various Gs. 

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