The classical GTPase cycle

Trimeric G proteins transmit signals from a huge group of heptahelical cell surface receptors to different categories of effectors such as enzymes and ion channels (Gilman 1987). The molecular diversity of trimeric G proteins signifies their pivotal role in numerous signal transduction pathways. To date, over twenty Ga, six G|3, and thirteen Gy subunits have been cloned (Hurowitz et al. 2000). The three subunits form two functional compartments— the Ga subunit and the stable G^y complex. Ga subunits belong to a group of enzymes known as GTP hydrolases (GTPases; Bourne et al. 1991). The GDP-bound form of Ga is associated with G^y in the resting stage. Ligand binding to an upstream receptor activates the GDP/GTP exchange of the Ga. GTP-induced conformational changes of Ga reduce its affinity for the G^y complex. Dissociation of GTP-bound Ga and G^y subunits allows their disparate interactions with effector molecules. GTP hydrolysis occurs in the Ga and returns it to the GDP-bound form with high affinity for G^y and receptors. This classical paradigm of trimeric G protein signalling (Fig. 4.1) has undergone substantial modifications in light of the discovery of novel signalling partners with new modes of signal modulation, such as the family of regulators of G protein signalling (RGS; see De Vries et al. 2000). In addition to a general account of their major properties, recent advances of G protein signalling are presented in this chapter.

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