G protein coupled receptors (GPCRs)

GPCRs are 7 transmembrane proteins found only in eukaryotes. Ligands include pheromones, hormones, neurotransmitters. The receptor was the focus of the 2012 Chemistry Nobel. Physiologically these receptors are involved in the senses, behavior and mod regulation, immune activity, and the nervous system.

A GPCR has 7 transmembrane helicies. Externally the receptor may be glycosylated and can have disulfide bonds between their conserved cysteine residues. Their C terminus is intracellular and N terminus is extracellular. The N Terminus often contains serine or threonine residues which increase affinity for beta-arrestins when phosphorylated or can induce translocation from the cell membrane. These beta-arrestins assist in scaffolding for protein complexes and prevent G-protein coupling. GPCRs can be targeted for lipid rafts via palmitoylation of the C terminal tail.

Pathway: Ligand binds GPCR causing a conformation change that activates its function as a GEF (guanine nucleotide exchange factor) which exchanges the bound GDP for a GTP on the associated G protein. This heterotrimeric G protein complex is bound to the GPCR in its inactive state. The Galpha protein-GTP dissociates and sends the signal downstream. To terminate the pathway GTP undergoes hydrolysis (GTPase can speed this process) to GTP and formation of the G protein complex resumes at the GPCR. There are two principle signal transduction pathways that utilize this type of singnaling:

  1. cAMP Signaling Pathway
    1. Gα activates binds adenylyl cyclase (an enzyme that converts ATP into cAMP)
    2. cAMP is known to activate PKA (protein kinase A) in humans
      1. it also regulates heart rate, cortisol secretion, and breakdown of fat.
  2. Phosphatidylinositol Signaling Pathway
    1. Gq proteins activate this line, Gβγ subunits are another minor form of activation.
    2. Protein Lipase C (PLC) hydrolyzes PIP2 into IP3 and DAG.
      1. IP3 can bind at the ER opening Ca2+ ion channels
      2. DAG helps activate PKC
    3. Phosphoinositides are phosphorylated (at sites 3, 4, and 5) and play roles in lipid signaling, cell signaling, and membrane trafficking.

Example Pathway: PIK3CA

PIK3CA (also p110alpha) is a class 1 PI(3)K, which are associated with cell proliferation and survival. PIK3CA uses ATP to phosphorylate PI4P and PIP2.

See Signaling Pathways for more information.

Example Pathway: Epinephrine

Epinephrine is released by the adrenal medulla during fasting (metabolic duress) to stimulate glycogenolysis. GPCR: adreneric receptor. α-adrenergic receptor is a Gq GPCR. β-adrenergic receptor is a Ga/s GPCR.

See the Epinephrine pathway here

Example Pathway: Wnt

A development pathway. See Signaling Pathways for more information. GPCR: Frizzled.

Example Pathway: Gaba