MODULE 27 - G-Protein-Linked Receptors PDF

MODULE 27 GPCRs – Definition Ligands: hormones, neurotransmitters, local mediators. One ligand can activate different receptors (e.g., adrenaline activates > 9 receptors, acetylcholine activates 5, serotonin - 15). The receptor polypeptide chain threads across the lipid bilayer seven times (s...

MODULE 27 GPCRs – Definition Ligands: hormones, neurotransmitters, local mediators. One ligand can activate different receptors (e.g., adrenaline activates > 9 receptors, acetylcholine activates 5, serotonin - 15). The receptor polypeptide chain threads across the lipid bilayer seven times (serpentine receptors). Examples: rhodopsin, a light-activated protein in the vertebrate eye, olfactory receptors in the vertebrate nose. ~50% of all known drugs work through G-protein-linked receptors. Trimeric G-Proteins Ligand binding induces a conformational change that activates trimeric GTP-binding proteins (G proteins). The G proteins are at the cytoplasmic face of the plasma membrane and couple the receptors to enzymes or ion channels. The G proteins are composed of α, β, and γ subunits; α and γ subunits have covalently attached lipid anchors. In an unstimulated state, the α subunit binds GDP. In the stimulated state, (1) the α subunit undergoes a conformational change, releases GDP, and binds GTP, and (2) the trimer dissociates into an α subunit and a βγ complex; both have signaling functions. Switching off the G-proteins The α subunit is a GTPase; once it hydrolyzes its GTP to GDP, it re-associates with the βγ complex to form an inactive heterotrimeric G protein. The time during which the α subunit and βγ complex remain apart and active is short; it depends on how quickly the α subunit hydrolyzes bound GTP. The GTPase activity of the α subunit is enhanced by the binding of its target effector protein or a regulator of G protein signaling (RGS). Thus, effectors and RGS proteins are α subunit-specific GTPase activating proteins (GAPs). Types of Heterotrimeric G Proteins Gα subunit type Effect of activated Gα on the target protein Gαs (stimulatory) Stimulation of adenylyl cyclase Gαi (inhibitory) Inhibition of adenylyl cyclase Gαq (activating the PI cascade) Stimulation of phospholipase C Gαt (inhibitory, for transducin) Stimulation of cGMP phosphodiesterase G Proteins That Signal via Cyclic (c) AMP cAMP is made from ATP by adenylyl cyclase, and it is destroyed by cAMP phosphodiesterase to adenosine 5′-monophosphate (5′-AMP). Extracellular signals usually increase cAMP levels by increasing the cyclase activity. Adenylyl cyclase is a transmembrane protein regulated by G proteins and Ca2+.