G Protein - coupled Receptors

Summary Sheet:

  • G protein coupled receptors are made of single polypeptide chains.

  • The chains are folded and embedded into cell membranes.

  • The chains fold seven times so 7 proteins are present in the cell membrane from one receptor.

  • the N domain = extracellular

  • the C domain = intracellular

  • the C domain is attached to a Stimulatory G protein or Gs

  • the Gs protein has 3 domains

1) beta subunit

2) alpha subunit

3) gamma subunit

  • the alpha subunit is attached to GDP = inactive form of Gs protein

Steps

  1. When a signalling molecule from the external environment binds to G protein-coupled receptor, the GDP attached to the alpha subunit is replaced with GTP = active form of Gs.

  2. The GTP is hydrolysed to GTF allowing the alpha subunit to move and attach to Adenylyl cyclase enzyme.

  3. The adenylyl cyclase enzyme catalyses the formation of cyclic AMP from ATP.

  4. The cyclic AMP activates AMP-dependent protein kinase A.

  5. The activated protein kinase A further activates other cellular proteins by phosphorylation.

  6. GTP attached to alpha subunit gets hydrolysed to GDP.

  7. GDP bound alpha subunit is inactive and returns to beta and gamma subunit which is still attached to G protein-coupled receptor.

G Protein coupled receptors

  • Gs - stimulates adenylate cyclase

  • Gi - inhibits adenylate cyclase

  • Gq - activates phospholipase C

Cyclic AMP (cAMP) acting as a second messenger

  • Adenylate cyclase converts ATP into cAMP

  • cAMP binds to activates other molecules like PKA

  • PKA (protein kinase) can phosphorylate other proteins, leading to various cellular responses,

Enzyme-linked receptors

  • cell surface receptors

  • have intracellular domains

2 types:

1) intracellular domain of receptor is an enzyme

2) intracellular domain interacts with an enzyme in order to catalyse a reaction

Kinase = enzyme that transfers phosphate groups to a protein or other target

Receptor Tyrosine Kinase (RTKs)

  • a class of enzyme-linked receptors found in humans and many other species

  • a receptor tyrosine kinase transfers phosphate groups specifically to the amino acid tyrosine

Receptor Tyrosine Kinase signalling

  1. signalling molecules bind to the extracellular domains of two nearby RTKs.

  2. ligand-binding induces the neighbouring RTKs to come together and dimerise.

  3. the dimerisation activates the receptors’ intracellular tyrosine-kinase domain and the receptors attach phosphates to tyrosine in each other’s intracellular domain.

  4. the phosphorylated tyrosine can transmit the signal to other molecules in the cell, initiating complex intracellular pathways.

Insulin Receptors

  1. Insulin molecules bind to the alpha-subunits of the insulin receptor.

  2. A conformational change occurs that activates the receptor’s tyrosine kinases

  3. The activated tyrosine kinases add phosphate groups to specific tyrosine residues on themselves (autophosphorylation)

  4. This activated receptor then phosphorylates other proteins, particularly insulin receptor substrates, which creates docking sites for more signalling molecules.

  5. Signalling pathways are initiated, including the Ras/MAPK pathway and the PI3K/Akt pathway.

  6. Cellular responses are triggered, such as moving the GLUT4 glucose transporter to the cell surface.

Intracellular Receptors

  • receptor proteins found on the inside of the cell, typically in the cytoplasm of nucleus

  • the ligands of intracellular receptors are typically small, hydrophobic molecules since they must be able to cross the plasma membrane to reach their receptors

Example:

  • the receptors for hydrophobic steroid hormones such as the sex hormones estradiol and testosterone

Nuclear Receptors (to trigger transcription of genes)

  • hormones like the steroid hormones are lipid soluble and can diffuse through the plasma membrane.

  • inside the cell they bind to their receptors, causing a conformational change.

  • the conformational change allows a dimer to form.

  • the dimer can then enter the nucleus

  • the dimer binds to recognition sites on DNA and triggers (or inhibits) transcription of specific genes