G Protein-Coupled Receptor (GPCR)

The GPCR complex is composed of two units: a receptor protein that binds to the chemical signal (the ligand) and the G protein complex associated with the inner side of the membrane (i.e., a peripheral protein complex). The GPCR has a ligand binding site on the external surface and a G protein binding site on the internal surface. The G protein complex is composed of three subunits: the alpha, beta, and gamma subunits. The alpha subunit has a site that can bind Guanosine Triphosphate (GTP) or Guanosine Diphosphate (GDP), hence the name G protein. In its inactive form, the G-alpha subunit is bound to GDP, and the three subunits (alpha, beta, and gamma) are bound together. When a ligand binds to the receptor on the surface of the cell, the G protein binding site changes shape, allowing the G protein to bind to the intracellular region of the receptor. This binding causes the G protein to then change shape, and the GDP exits the binding site on the alpha subunit and is replaced by a GTP from the cytoplasm. The binding of GTP causes the alpha subunit to separate from the other two subunits (beta/gamma dimer). Once separated, the alpha subunit (and sometimes the beta/gamma dimer) can then bind to and activate other proteins inside the cell. The mechanism of action is typically mediated by one of two enzymes: adenylate cyclase or phospholipase C. Cellular responses include activation of metabolic enzymes, opening or closing ion channels, turning on transporters, initiating gene transcription, regulating motility, regulating contractility, stimulating secretion, and even controlling memory. After a short period of time, the G-alpha subunit hydrolyzes the GTP into a GDP and phosphate, allowing it to reunite with the beta/gamma dimer, turning off the signal. To date, approximately 800 genes for G protein-coupled receptors have been identified. 

Adenylate cyclase

Activation of Adenylate cyclase results in the synthesis of a second messenger molecule called cyclic adenosine monophosphate (cAMP). The primary action of cAMP is to activate the enzyme protein kinase A (PKA). PKA phosphorylates serine and threonine residues of proteins which can lead to activation.

Phospholipase C

Activation of the phospholipase C results in the cleavage of a membrane phospholipid called Phosphatidylinositol bisphosphate (PIP2). This enzymatic cleavage yields two molecules: diacylglycerol (DAG) and inositol triphosphate (IP3). DAG remains in the membrane and activates another enzyme called protein kinase C (PKC) while IP3 diffuses into the cytoplasm and acts as a ligand for calcium channels on the endoplasmic reticulum.


The ion calcium is a very common intracellular second messenger. Intracellular Ca++ levels are kept very low because of various secondary and primary active pumps. This is because Ca++ has potent effects on a variety of different protein activities. Muscle cell proteins are particularly sensitive to Ca++.

G-Protein Mechanism

Ligand Activation and G-Protein Effect. Image drawn by JS Fall 2014

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