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G-Protein Receptors

A G-protein linked receptor is an integral plasma protein with an amino acid sequence containing several hydrophobic alpha-helices that cross the plasma membrane seven times. The alpha-helices are linked to each other by four extracellular and four intracellular chains of polar amino acid residues. The N-terminus of the protein is in the first extracellular chain, while the C-terminus is in the last cytosolic chain. Ligands bind to one of the extracellular chains while the cytosolic chains interact with a cytosolic membrane protein (the G-protein). When the receptor is bound to its substrate, a conformational change allows the receptor to bind to the G-protein.

There are two G-protein subclasses: heterotrimeric and single unit. The heterotrimeric G-protein contains three subunits: alpha, beta y gamma. The alpha and gamma subunits are bound to the inner face of the plasma membrane by lipid tails. The gamma subunit binds beta, which in turn binds alpha. An example of a heterotrimeric G-protein is the cytoplasmic protein that interacts with the beta-adrenergic receptor.

Ras is an example of a single unit G-protein. Both heterotrimeric and single unit G-proteins are activated by binding GTP, which is quickly hydrolyzed to GDP, inactivating the protein.

Enzymes activated by G-proteins usually start a signal transduction cascade, using many sequential factors, most of them enzymatic. Many reactions of a given type occur in a very short period of time. This translates into a multi-step signal transduction cascade, causing signal amplification and allowing multiple responses from a single ligand in a given cell..

When no ligand is bound to the receptor of an heterotrimeric G-protein, alpha is bound to GDP and complexed with beta and gamma. Binding of substrate to the receptor changes its conformation, causing it to bind to the G-protein in such a way that GDP is displaced and GTP is bound. The alpha-GTP complex dissociates from beta-gamma and binds to an enzyme. In the case of the beta-adrenergic receptor, it binds to and activates adenylyl cyclase. This activation is short lived because alpha hydrolyzes GTP in seconds, leading to association of alpha with beta-gamma after activating adenylyl cyclase..

Adenylyl cyclase converts ATP to cAMP, a second messenger that carries on an amplified signal transduction cascade. cAMP binds cAMP-dependent protein kinase (PKA) at its regulatory subunits. When the regulatory subunits of PKA are bound, the catalytic subunits are released and enter the nucleus, where they phosphorylate CREB. Phosphorylated CREB together with CBP/P300 activate the transcription of genes containing CREB response element (CRE) in the promoter.

Some heterotrimeric G-proteins are inhibitory proteins. Using the same mechanism as stimulatory G-proteins, an inhibitory ligand binds its receptor, which in turn activates an inhibitory G-protein. The G-protein's mechanism is the same as before except that binding to, for example adenylyl cyclase, inhibit enzyme activity.

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