caffeine signaling via ligand-receptor binding agonist - ligand binding to a receptor and eliciting...
TRANSCRIPT
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N
N N
N
CH3H3C
O
O
CH3
caffeine
Signaling via Ligand-Receptor Binding
Agonist - ligand binding to a receptor and eliciting a response
Antagonist - ligand binding to a receptor but not eliciting a response
R + L ↔ R∙L
Kd = [R][L]/[R∙L]
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Bacterial Quorum Sensing
Increased cell density dependant signaling
Activation of Bio-film formation which affects bacterial resistance
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Extracellular Signals
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G Protein Coupled Receptors
Guanyl nucleotide binding protein:Minus ligand, α, β, and γ subunits associated with GDP (inactive bound form) and
Plus ligand, α subunit exchanges for GTP (active released form)
Signal propagation: Activate adenylate cyclase converts ATP to cyclic ATP
Signal resetting:GTP hydrolyzed to GDP and β, and γ subunits re-associate
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G-Protein Cycle and Generation of Cyclic AMP
How is adenylate cyclase activated?
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External Signal for G-Protein Activation
β2-adreneric receptor
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Heterotrimeric G Protein
α, β, and γ subunits (blue, green, and yellow, respectively) associated with GDP (orange)
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G-Protein Pathway Activation by Epinephrine
What is effective signaling? Specificity? Sensitivity?
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Adenylate Cyclase Activation/Deactivation
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Cyclic AMP Deactivation
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Protein Kinase A Activation by cAMP
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Protein Kinase A Regulation by Phosphorylation
Dephosphorylation blocks substrate from active site
Catalytic subunit: light green
Activation loop: dark green
Substrate target protein: blue
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External Signal for G-Protein Activation
α-adreneric receptor is also activated by epinephrine and norepinephrine
IP3, a product of phosphatidylinositol bisphosphate hydrolysis signals a calcium influx and protein kinase C activation
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Phosphoinositide Cascade
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Calcium Binding Protein: Calmodulin
EF-hand protein familyExtended unbound form
Bent bound to a target protein
Ca+2 ions
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Receptor Tyrosine Kinases
Operative for certain hormones and signaling molecules that regulate growth (e.g. insulin)
Ligand binding allows the receptor monomer to form a dimer unit with cytoplasmic kinase domain catalytically active
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Insulin receptor
Insulin binding site
Insulin binding site
Extracellular region
Cell surface
α,β subunits: one in space-filling (red) and other in backbone-trace form (yellow)
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Insulin Receptor Tyrosine Kinase Activation
Inactive form (blue)
Activation loop (dark blue)
Active form (green)
Activation loop (dark green)
Note:Activation loop swings out with Tyr phosphorylation
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Ras- rat sarcoma virus
Ras Signal Transduction Pathway
Color coding: red inactive; green active
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Ras Signal Transduction Pathway
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Ras Signal Transduction Pathway
Protein phosphorylation can lead to subsequent gene activation
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Lipid Hormone Signaling
Includes thyroid hormones that stimulate metabolism (right) as well as hormones for salt, water and reproductive functions
Do not bind to cell-surface receptors
Directly cross membranes to interact with intracellular receptors
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Lipid Hormones: Eicosanoids
Regulation of blood pressure, blood coagulation, inflammation, pain and fever
Aspirin inhibits cyclooxygenase activity and therefore serve as a blood thinner