NE102 Lecture Notes 3

Common structure seven transmembrane domains

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G protein-couple receptors have a common structure and mechanism of activation. Common structure Seven-transmembrane domains Extracellular domain containing ligand-binding site Cytosolic domain that initiates signaling when receptor is ligand-bound Mechanism of activation Activation of G protein-coupled receptors requires activation of  G proteins. QUESTION: What are G proteins? Heterotrimetric GTP-binding proteins (3 different polypeptides that bind GTP) Bound & regulated by G protein-coupled receptors Ligand-binding  stimulates  GEF activity of the receptors Activation of G proteins entails dissociation of alpha & beta/gamma subunits GTP hydrolysis by GAPs converts G protein back to inactive state  QUESTION: How do active G proteins affect cell behavior?  Major effect = the generation of a second messenger called cyclic AMP (cAMP) from  ATP Form protein-protein interactions with adenylyl cyclase Referred to as second messenger because ligand is first messenger
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Cell Signaling con’t. 18:04 QUESTION: How does the generation of cAMP affect cell behavior? Primary target for cAMP = Protein Kinase A (aka PKA) Binding of cAMP to the regulatory subunits releases and activates the catalytic subunits QUESTION: Once active, how does PKA affect cell behavior? Major target of cAMP and PKA signaling = CREB In addition to LTP, CREB regulates expression of numerous genes involved in cell  proliferation, cell survival, and differentiation.  PKA phosphorylates numerous substrates in addition to CREB GPCRs = our odorant receptors The ligand for many = odorants (therefore odorant receptors) QUESTION: How can GPCR activation lead to an action potential? Olfactory neurons also express cAMP-regulated ion channels RECEPTOR PROTEIN-TYROSINE KINASES (RTKs) RTKs = the receptors for most growth factors that control cell profileration and survival 3 domains N-terminal extracellular ligand-binding domain Single transmembrane a-helix C-terminal cytoplasmic domain w/ protein-tyrosine kinase activity QUESTION: How do single-pass transmembrane proteins convey information across a  membrane? RTK activations begins with receptor dimerization – autophosphorylation The TRK phospho-tyrosine residues = binding sites that activate downstream signaling  proteins
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Cell Signaling con’t. 18:04 There are many downstream signaling molecules that  Bind specific activated RTKs Activate specific signal transduction pathways One key signal transduction pathway activated by RTKs –  the MAP kinase pathway MAP KINASE PATHWAY Ligand -> RTK -> Ras -> Raf -> MEK -> ERK -> various targets Ras gets activated Ras = GTP-binding protein that is localized at the plasma membrane (always stuck  there) GEFs convert Ras to its active state by catalyzing exchange GDP for GTP
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