caffeine signaling via ligand-receptor binding agonist - ligand binding to a receptor and eliciting...

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]

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

β2-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

IP3, a product of phosphatidylinositol bisphosphate hydrolysis signals a calcium influx and protein kinase C activation

Phosphoinositide Cascade

Calcium Binding Protein: Calmodulin

EF-hand protein familyExtended 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

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

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