Table 1 Known functions of the major proteins involved in the mammalian G protein-coupled receptor (GPCR) signaling pathway as defined by the human gpDB[21]

Adenylate cylcase

Transmembrane protein regulated by G protein; catalyzes formation of the second messenger cyclic adenosine monophosphate (cAMP) from ATP.

ATP-sensitive inward rectifier K + channels

Regulated by G proteins and GRKs. Activation leads to hyperpolarization and reduction of membrane excitability.

G protein (Gα,β,γ)

Heterotrimeric protein composed of α,β, and γ subunits; activated by GPCR to bind to and activate/deactivate various effectors (e.g. second messengers); amplifies receptor signal. The α-subunit is divided into several sub-types that perform different functions by activating various effector proteins: α(q) activates PLC, α(s) activates the cAMP-dependent pathway via activation of AC, α(i) inhibits AC and thus cAMP production and α(12/13) activates Rho GTPases.

G protein-coupled receptor (GPCR)

Cell surface receptor; binds agonist/ligand, catalyzing exchange of GDP for GTP on G protein; dissociates and activates G protein subunits.

GPCR kinase (GRK)

Regulates GPCR activity via phosphorylation; desensitizes the receptor signal.

Phosphodiesterase

Degrades the phosphodiester bond in the second messengers cAMP and cGMP; terminates receptor signal.

Phosphoinositide-3 kinase (PI3K)

Recruited to the cell membrane following GPCR activation; binds G protein and initiates assembly of signaling complexes and priming of protein kinase cascades; hyperactivation of this pathway has been associated with cancer and diabetes.

Phospholipase C

Catalyzes hydrolysis of phospholipids to generate the second messengers inositol 1,4,5-triphosphate (IP3) and diacylglycerol (DAG); amplifies signal by stimulating Ca²⁺ release and protein kinase activation.

Protein kinase C

Regulates signal transduction; activated by G proteins or increases in cytosolic Ca²⁺; phosphorylates a wide variety of proteins including small GTPases and MAPKs

Raf

Member of the serine/threonine-specific protein kinases that functions downstream of the Ras subfamily. Raf activates the MAPK/ERK pathway.

Rap1GAP

Encodes a GTPase-activating protein that down-regulates the activity of the RAP1 protein. RAP1 is a Ras subfamily protein.

RasGAP

Stimulates the GTPase activity of Ras, thereby inactivating Ras. Ras acts as a molecular switch, functioning within a signal transducing cascade of reactions.

Regulator of G protein signaling (RGS)

Inactivates G protein, leading to rapid turnoff of GPCR signaling. RGS promotes GTP hydrolysis by the G protein α-subunit.

RhoGEF

Structural domain of guanine nucleotide exchange factors for Rho-like GTPases that controls Rho signaling by mediating GDP release from Rho and replacing with GTP.

Rho small GTPases

Family of small signaling G proteins that are homologous to Gα subunit but are monomeric in structure. These proteins interact with and activate effector proteins that mediate downstream signaling.

SHC transforming proteins

Src homology 2 domain containing protein. Links activated tyrosine receptor kinases to the Ras pathway.

Tyrosine receptor kinases

Cell surface receptor that link GPCRs to the Ras-MAPK pathway. Activated by the G protein βγ subunit and in turn stimulates the Ras subfamily proteins.

Voltage dependent Ca2+ channels

Modulates calcium influx into the cell. GPCRs play critical role in negative feedback to inhibit the activity of these channels via direct interaction with the G protein βγ subunit.