Second Messengers and Signal Transduction

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Second Messengers and Signal Transduction

• Tim Bloom, Ph.D.
• 206 Maddox Hall
• 893-1712

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Overview

• Signal transduction- a concept
• Second messengers
• Characteristics
• Examples
• Benefits

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Review to Date

• Cells respond to specific molecules
• Generic name ligand
• Brand names acetylcholine, nicotine, insulin, etc
• Receptors recognize ligands
• Specific interaction based on shape and bonds
• Receptors respond to agonist ligands
• Response depends on specific nature of receptor
• Change in receptor activity is a signal

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Signal Transduction

• Intracellular communication
• Detection of extracellular event
• Generation of internal change
• Bottom line- presence of external ligand causes a
  change inside cell

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Signaling Examples

• Ligands
• Estrogen
• Acetylcholine
• Insulin
• Epinephrine

• Receptors
• Transcription factor
• Sodium channel
• Receptor kinase
• G protein-coupled receptor

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Second Messengers

• Molecules whose presence is a signal
• Synthesized or released from storage
• Act as intracellular ligands
• Commonly used in G protein-coupled receptor
  signaling
• Made or released by effector proteins
• (Ligand for GPCR is 1st messenger)

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Second Messengers

• General characteristics
• Low amounts in resting state
• Regulated synthesis (or release)
• Regulated destruction (or removal)
• Act on intracellular proteins as agonists

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Second Messengers

• Cyclic nucleotides
• cGMP
• cAMP
• Calcium
• Lipid derivatives
• IP3
• DAG
• Many others

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Cyclic GMP

• Made from GTP
• Guanylate cyclase
• Membrane or soluble
• Acts as receptor
• Hydrolysis of cGMP to GMP terminates signal

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cGMP

• Regulates several proteins as agonist
• Ion channel
• Protein kinase
• Important in smooth muscle relaxation
• Viagra interferes with cGMP hydrolysis
• Increases cGMP
• Prolongs cGMP signal

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Cyclic AMP

• Made from ATP
• Adenylate cyclase
• Membrane only
• Not a receptor
• Hydrolysis of cAMP to AMP terminates signal

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cAMP

• Regulates some ion channels as agonist
• Regulates a kinase
• Phosphorylates many substrates
• Substrate determines effect seen
• Increase glycogen breakdown
• Increase cardiac beat strength
• Etc.

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cAMP System

• Example of typical second messenger set up
• Receptor
• G protein
• Effector protein
• Second messenger
• 2nd Messenger binding protein(s)
• Target(s) of SMBPs

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cAMP Signaling Path
E
epinephrine
Gs
R
cAMP
ATP
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cAMP Signaling Path
E
epinephrine
Gs
R
cAMP

ATP
PKA
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cAMP Signaling Path
E
epinephrine
Gs
R
cAMP

ATP
PKA
Substrate-P
substrate
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Calcium as a 2nd Messenger

• Low cytoplasmic Ca at rest
• Channels open with voltage and/or ligands
• Channels in PM and in calciosome

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Calcium as a 2nd Messenger

• High cytoplasmic Ca when stimulated
• Pumps move calcium out of cytoplasm
• Pumps in PM and in calciosome

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Calcium as a 2nd Messenger

• Many binding proteins mediate Ca action
• Activated by calcium
• Troponin C
• Calmodulin
• Calmodulin is multifunctional

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Calmodulin Targets

• Cyclic AMP metabolism
• Adenylate cyclase (some versions)
• Phosphodiesterase (some versions)
• Protein phosphorylation
• Calmodulin-dependent kinases
• Calcineurin (a phosphatase)
• And others

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Phospholipase C as Effector

• Inositol tri-phosphate
• Hydrophilic
• Agonist for internal calcium channel
• Cai rises
• Multiple effects through Ca-binding proteins

• Diacylglycerol (DAG)
• Hydrophobic
• Mimicked by phorbol esters (tumorogenic)
• Targets PKC (a kinase)
• PKC requires Ca and DAG

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IP3/DAG Signaling Path
PKC
E
muscarine
G
R
Substrate-P
substrate
IP3 DAG
PI
Ca
calciosome
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Why 2nd Messengers?

• Complicated pathways
• Difficult to understand
• Hard to learn
• Many parts makes easy to be disrupted
• Complexity allows flexibility
• More graded cellular responses
• Interaction of pathways
• Signal amplification

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Signals and Effects

• Signal is required to produce cellular change
• Signal generated by receptor (or effector)
• Signal size related to of active receptors
• (dose response!)

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Signal Amplification

• Example from G protein-coupled receptor
• Activated receptor hits several G proteins
• Each effector makes/ releases many molecules
• 2nd messenger receptor also amplifies, especially
  if its a kinase
• Bottom line one molecule of extracellular ligand
  generates many modified proteins inside the cell
  ( a large signal)

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Review

• Ligand binding alters receptor
• Some receptors use signaling molecules
• Synthesized from precursors
• Released from storage site
• Called second messengers
• Second messengers activate other proteins
• Activation acts as signal, changes things
• Second messenger is removed to end signal