G-proteins, short for guanine nucleotide binding proteins, are a family of proteins involved in second messenger cascades. They are so-called because of their signaling mechanism, which uses the exchange of guanine diphosphate (GDP) for guanine triphosphate (GTP) as a molecular "switch" to allow or inhibit biochemical reactions inside the cell. Alfred Gilman and Martin Rodbell were awarded the Nobel Prize in Physiology or Medicine in 1994 for their discovery and research on G-proteins.
G-proteins belong to the larger grouping of GTPases. "G-protein" usually refers to the membrane-associated heterotrimeric G-proteins, sometimes referred to as the "large" G-proteins. These proteins are activated by G-protein coupled receptors and are made up of alpha (±), beta (²) and gamma (³) subunits. There are also "small" G proteins or small GTPases like ras that are monomeric and not membrane-associated, but also bind GTP and GDP and are involved in signal transduction.
G-proteins are perhaps the most important signal transducing molecules in cells. In fact, diseases such as diabetes, alcoholism, and certain forms of pituitary cancer, among many others, are thought to have some root in the malfunction of G-proteins, and thus a fundamental understanding of their function, signaling pathways and protein interactions may lead to eventual treatments and possibly the creation of various preventative approaches.
Receptor activated G-proteins are bound to the inside surface of the cell membrane. They consist of the G± and the tightly associated G²³ subunits. When a ligand activates the G-protein coupled receptor, the G-protein binds to the receptor, releases its bound GDP from the G± subunit, and binds a new molecule of GTP. This exchange triggers the dissociation of the G± subunit, the G²³ dimer, and the receptor. Both, G±-GTP and G²³, can then activate different 'signalling cascades' (or 'second messenger pathways') and effector proteins, while the receptor is able to activate the next G-protein. The G± subunit will eventually hydrolize the attached GTP to GDP by its inherent enzymatic activity, allowing it to reassociate with G²³ and starting a new cycle.
A well characterized example of a G-protein triggered signalling cascade is the cAMP pathway. The enzyme adenylate cyclase is activated by G±s-GTP and synthesizes the second messenger cyclic adenosine monophosphate (cAMP) from ATP. Second messengers then interact with other proteins downstream to cause a change in cell behavior.
G± subunits consist of two domains, the GTPase domain, and the alpha-helical domain. There exist at least 20 different alpha subunits, which are separated into several main families:
- G±s or simply Gs (stimulatory) - activates adenylate cyclase to increase cAMP synthesis
- G±i or simply Gi (inhibitory) - inhibits adenylate cyclase
- Golf (olfactory) - couples to olfactory receptors
- Gt (transducin) - transduces visual signals in conjunction with rhodopsin in the retina
- Gq - stimulates phospholipase C
- The G12/13 family - important for regulating the cytoskeleton, cell junctions, and other processes related to movements
The ² and ³ subunits are closely bound to one another and are referred to as the beta-gamma complex. The G²³ complex is released from the G± subunit after its GDP-GTP exchange. The free G²³ complex can act as a signaling molecule itself, by activating other second messengers or by gating ion channels directly. For example, the G²³ complex attached (?) to histamine receptors can activate phospholipase A2. G²³ complexes attached (?) to muscarinic acetylcholine receptors, on the other hand, directly open G-protein coupled inward rectifying potassium (GIRK) channels.
- Kandel, Eric, James Schwartz, and Thomas Jessel. 2000. Principles of Neural Science. 4th ed. McGraw-Hill, New York.
- Voet, Donald and Judith G. Voet. 1995. Biochemistry 2nd ed. John Wilely & Sons, New York.