ABSTRACT
The discovery of a single molecule, adenosine 3¢,5¢-cyclic monophosphate (cyclic AMP, cAMP), by Nobel Prize winner Sutherland (1971) and his colleagues in 1958 constituted a seminal moment in biochemistry, heralding the birth of many of the current concepts of both biological signaling between cells and metabolic regulation.1 The original second messenger concept was that hormones and neurotransmitters, the primary biochemical messengers, are recognized by, and bind to, speci c cell membrane receptors.2 This binding indirectly stimulates adenylyl cyclase that is responsible for the synthesis of the second(ary) messenger, cAMP, which is subsequently released into the cell (Figure 4.1). This concept is now extended to include two separate populations of such membrane receptors; Rs, which on binding of the agonist stimulates the cyclase, and Ri, which inhibitsit. They each have a characteristic serpentine (or seven-pass) structure that crosses the membrane seven times.3 G-proteins are sited between the receptors and adenylyl cyclase and are the means of transducing the signal from receptor to cyclase.4 G-proteins are heterotrimeric GTP-binding proteins that undergo a sequential cycle of events: interaction with the stimulated receptor leads to the binding of GTP, followed by G-protein dissociation into a and bg subunits; interaction of this released
the a subunit with the adenylyl cyclase, affecting the latter’s activity, then GTP conversion to GDP, followed by G-protein reassociation into the trimer with consequent loss of interaction with the cyclase.
