Coupling To G Proteins

The classical mechanism by which GPCRs are functionally active is defined by their coupling to guanine nucleotide-binding proteins or G proteins.7 Typically, a GPCR is in its resting or low affinity state in the absence of agonists. The binding of an agonist to a receptor triggers a modification in the receptor conformation and the formation of a complex with the intracellular G proteins (Figure 2.1). The hetero-trimeric G protein consists of a membrane-associated Ga subunit and the more

Cellular responses angiogenesis, cancer, cell survival, development, differentiation, proliferation

Second messengers

Cellular responses angiogenesis, cancer, cell survival, development, differentiation, proliferation

Second messengers

FIGURE 2.1 GPCR signalling through G proteins. The interaction with agonist leads to a conformational change of the receptor and the coupling to G proteins. One consequence is the activation of a signal transduction cascade through the Ga subunit. Also, Gp and Gg can induce activation of cellular responses. A = agonist or antagonist. DAG = diacylglycerol. PI3Kg = phosphoinositide 3-kinase-g PLCP = phospholipase Cp. PKA = protein kinase A. PKC = protein kinase C.


G Proteins and Signal Transduction Events They Mediate

G protein Signal Transduction Reference

Gaq, Gall Phospholipase C activation; regulation of phosphoinositide- 44

specific phospholipase C activity

Ga14, Ga15, Ga16 Rho GEF activation 45

Gas Adenylyl cyclase activation; RGS-PX1 acts as a GTPase-activating 46 protein for Gas

Gaolf Calcium channel interaction; c-Src tyrosine kinase induction 47

Gai Adenylyl cyclase inhibition; induction of c-Src tyrosine kinase 48, 49

Gao K+ channel activation; increase in K+ leads to hyperpolarization 50

Gaz Cellular cross-talk through Rap1GAP1 51

Ga12 Rho activation 52

Ga13 E-Cadherin; p-catenin release 53

GaT transducin cGMP phosphodiesterase increase 54

Gagust gustiducin Taste-cell specific G protein, closely related to transducin 55

Gpg Activation of GIRK K+ channels 8

GIRKs Adenylyl cyclase activation; phospholipase C activation 56, 57

mobile Gp and Gg subunits. Modern genomic analysis has made it possible to identify several G protein subunits to reach the current number of 16 Ga, 5 Gp and 12 Gg subunits that have been cloned and sequenced.3 The Ga subunit binds GTP and GDP and is responsible for GTP hydrolysis. The Gp and Gg subunits form a pg complex to a stoichiometry of one to one.

After the interaction of GPCR and G protein is established, GDP is released and replaced by GTP, after which the Ga subunit is dissociated from the Gpg dimer. Both the Ga subunit and the Gpg dimer can activate cellular effector molecules. For example, Ga can activate adenylyl cyclase, resulting in increased cyclic AMP (cAMP) levels, which in turn can induce protein kinase A (PKA) activation. PKA is a serine-threonine kinase that phosphorylates transcription factors, other kinases, and GPCRs.

The different types of Ga subunits play crucial roles in signal transduction and can be divided into four groups. The Gas subunit is involved in the stimulation of adenylyl cyclase, whereas the Gai subunit functions in the inhibition of adenylyl cyclase and the activation of GIRK (G protein-coupled inwardly rectifying potassium) channels.8 Gaq is responsible for phospholipase C activation and Ga12 activates the Rho guanidine nucleotide exchange factors (GEFs). The Gpg dimers can independently activate GIRK channels, adenylyl cyclase, and phospholipases. Additional functions of G protein subunits are summarized in Table 2.1.

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