Caffeine Signaling via Ligand-Receptor Binding Agonist - ligand binding to a receptor and eliciting a response Antagonist - ligand binding to a receptor.

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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 K d = [R][L]/[R∙L]

Bacterial Quorum Sensing Increased cell density dependant signaling Activation of Bio-film formation which affects bacterial resistance

Extracellular Signals

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

G-Protein Cycle and Generation of Cyclic AMP How is adenylate cyclase activated?

External Signal for G-Protein Activation β 2 -adreneric receptor

Heterotrimeric G Protein α, β, and γ subunits (blue, green, and yellow, respectively) associated with GDP (orange)

G-Protein Pathway Activation by Epinephrine What is effective signaling? Specificity? Sensitivity?

Adenylate Cyclase Activation/Deactivation

Cyclic AMP Deactivation

Protein Kinase A Activation by cAMP

Protein Kinase A Regulation by Phosphorylation Dephosphorylation blocks substrate from active site Catalytic subunit: light green Activation loop: dark green Substrate target protein: blue

External Signal for G-Protein Activation α-adreneric receptor is also activated by epinephrine and norepinephrine IP 3, a product of phosphatidylinositol bisphosphate hydrolysis signals a calcium influx and protein kinase C activation

Phosphoinositide Cascade

Calcium Binding Protein: Calmodulin EF-hand protein family Extended unbound form Bent bound to a target protein Ca +2 ions

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

Insulin receptor Insulin binding site Extracellular region Cell surface α,β subunits: one in space- filling (red) and other in backbone-trace form (yellow)

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

Ras- rat sarcoma virus Ras Signal Transduction Pathway Color coding: red inactive; green active

Ras Signal Transduction Pathway

Protein phosphorylation can lead to subsequent gene activation

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

Lipid Hormones: Eicosanoids Regulation of blood pressure, blood coagulation, inflammation, pain and fever Aspirin inhibits cyclooxygenase activity and therefore serve as a blood thinner