G protein-coupled receptor signaling: implications for the digestive system

Extracellular signaling molecules regulate intracellular events by way of complex transduction assemblies composed of several proteins: receptor, G protein, effector, inactivating enzyme. Much is known about the structure and function of these transducer proteins. A signaling molecule initiates transduction by binding to the receptor which then prompts the G protein to undergo a reaction cycle. This cycle involves guanine nucleotide binding and hydrolysis, G protein subunit dissociation, and interactions with an effector (e.g. adenylyl cyclase, phospholipase C), as well as with inactivating molecules. The result is altered generation of intracellular second messengers, protein transcription, or another profound cellular response. This signal transduction system also contains multiple mechanisms for turning off the signal such as phosphorylating, internalizing, or downregulating receptors, uncoupling the receptor-G protein complex, or cell-surface peptidases, and precipitating conformational changes in transducer elements. These aspects of signal transduction are examined in two well studied systems, namely the beta 2-adrenergic and the substance P transducers. Both complexes are important physiological neuroregulators in the gut and elsewhere. Pathophysiological mechanisms involving aberrent signal transduction have been implicated in various diseases including major common illnesses such as heart failure and gastrointestinal disorders such as cholera, other infectious diarrheas, and colitis.