G-Protein-Linked Receptors Overview

Study Notes

G-protein-linked receptors are the largest family of cell-surface receptors in mammalian cells.
They mediate responses to a wide variety of extracellular signals like hormones, local mediators, and neurotransmitters.

SLO#1: List the pathways of signal transduction to generate various physiological responses.
SLO#2: Describe the role of G proteins in activating specific effector proteins.
SLO#3: Define primary and secondary messengers and provide specific examples of each.

All G-protein-linked receptors are single polypeptide chains that pass through the cell membrane seven times.
The structure is similar across many receptor types.

An extracellular signal molecule binds to a seven-pass transmembrane receptor.
The receptor protein undergoes a conformational change.
The receptor activates a G protein located on the underside of the plasma membrane.

G-proteins are heterotrimeric, comprising α, β, and γ subunits.
The α subunit binds to GTP and can hydrolyze it to GDP + Pi.
The α and γ subunits have lipid anchors that attach them to the plasma membrane's cytosolic surface.

G-proteins are switches turned on by receptors.
Different G proteins are specific for particular receptor/target protein combinations.
There are two major subclasses of trimeric G-protein-activated pathways:
- Adenylyl cyclase.
- Phospholipase C.

Adenylyl cyclase (AC) is a transmembrane protein with a cytosolic catalytic site.
AC produces cyclic AMP (cAMP), a small intracellular signaling molecule.
Phospholipase C produces inositol triphosphate (IP3), and diacylglycerol, other small intracellular signalling molecules.

GTP hydrolysis inactivates the α subunit, allowing it to rejoin the βγ complex, returning the system to its inactive state.

In the absence of a ligand, the α subunit binds GDP, and the α, β, and γ subunits are assembled in an inactive state.

The Ga-GTP subunit dissociates from the inhibitory βγ complex.
The Ga-GTP subunit stimulates adenylyl cyclase, increasing the synthesis of cAMP.
cAMP activates protein kinase A (PKA).

Ca2+ plays a key role as an intracellular messenger.
Ca2+ effects are often indirect, mediated through Ca2+ binding proteins like calmodulin.

Certain extracellular signals stimulate phospholipase C instead of adenylyl cyclase.
Phospholipase C cleaves a membrane phospholipid, producing diacylglycerol and inositol triphosphate (IP3).
IP3 releases Ca2+ from intracellular stores; Ca2+ triggers further responses.
Diacylglycerol activates protein kinase C.

Signal amplification: Enzyme cascades amplify the cell's response by expanding the signal.
Signal specificity: Different cells have different collections of proteins which allow for cells to response to different signals.
Cell signaling efficiency: Scaffolding proteins increase signal transduction efficiency by bringing proteins in the same pathway together.
Signal termination: Inactivation mechanisms, including the hydrolysis of GTP to GDP on the G protein and the removal of the receptor, revert the system to an inactive state.

Cholera toxin permanently activates Gs proteins, causing persistent cAMP production and severe diarrhea.

G-protein coupled receptors (GPCRs) are involved in a wide range of cellular functions.
Stimulation of GPCRs activates G protein subunits.
Some G proteins regulate ion channels, and others activate membrane-bound enzymes.
The cAMP and inositol phospholipid pathways, both utilize specific second messengers to control cellular processes.