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Second Messengers and Signal Transduction. Tim Bloom, Ph.D. 104A Hall of Science 893-1712. Overview. Signal transduction- a concept Second messengers Characteristics Examples Benefits . Signal Transduction. Intra cellular communication Detection of extracellular event

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second messengers and signal transduction

Second Messengers and Signal Transduction

Tim Bloom, Ph.D.

104A Hall of Science

893-1712

overview
Overview
  • Signal transduction- a concept
  • Second messengers
    • Characteristics
    • Examples
    • Benefits
signal transduction
Signal Transduction
  • Intracellular communication
    • Detection of extracellular event
    • Generation of internal change
  • Bottom line- presence of external ligand causes a change inside cell
signaling examples
Ligands

Estrogen

Acetylcholine

Insulin

Epinephrine

Receptors

Transcription factor

Sodium channel

Receptor kinase

G protein-coupled receptor

Signaling Examples
second messengers
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)
second messengers6
Second Messengers
  • General characteristics
    • Low amounts in resting state
    • Regulated synthesis
    • Regulated destruction
    • Act through other proteins
second messengers7
Second Messengers
  • Cyclic nucleotides
    • cAMP
    • cGMP
  • Calcium
  • Lipid derivatives
    • IP3
    • DAG
    • Many others
cyclic amp
Cyclic AMP
  • Made from ATP
  • Adenylate cyclase
    • Membrane effector
    • Needs a G-protein
  • Hydrolysis of cAMP to AMP terminates signal
slide9
cAMP
  • Regulates some ion channels as ligand
  • Regulates a kinase
    • Phosphorylates many substrates
    • Substrate determines effect seen
      • Increase glycogen breakdown
      • Decrease glycogen synthesis
      • Increase cardiac beat strength
      • Etc.
camp system
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”
    • Termination mechanism
camp signaling path12
cAMP Signaling Path

E

Gs

R

cAMP

+

ATP

PKA

camp signaling path13

PDE

-

cAMP Signaling Path

E

Gs

R

cAMP

+

ATP

PKA

Substrate-P

substrate

cyclic gmp
Cyclic GMP
  • Made from GTP
  • Guanylate cyclase
    • Membrane or soluble
    • Acts as receptor
    • No G-protein involved
  • Hydrolysis of cGMP to GMP terminates signal
slide15
cGMP
  • Regulates several proteins as ligand
    • Ion channels
    • Protein kinase
  • Important in smooth muscle relaxation
  • Important in visual system
calcium as a 2 nd messenger
Calcium as a 2nd Messenger
  • Low cytoplasmic Ca++ at rest
  • Channels open with voltage and/or ligands
  • Channels in PM and in “calciosome”
calcium as a 2 nd messenger17
Calcium as a 2nd Messenger
  • High cytoplasmic Ca++ when stimulated
  • Pumps move calcium out of cytoplasm
  • Pumps in PM and in “calciosome”
calcium as a 2 nd messenger18
Calcium as a 2nd Messenger
  • Many binding proteins mediate Ca++ action
  • Activated by calcium
    • Troponin C
    • Calmodulin
  • Calmodulin is multifunctional
calmodulin
Calmodulin

Ca++

Ca++

Ca++

Ca++

calmodulin20
Calmodulin

Ca++

Ca++

Ca++

Ca++

calmodulin targets
Calmodulin Targets
  • Adenylate cyclase (some versions)
  • Phosphodiesterase (some versions)
  • Myosin light chain kinase
  • Calmodulin-dependent kinases
  • Calcineurin (a phosphatase)
  • And so on…
phospholipase c as effector
Inositol tri-phosphate

Hydrophilic

Agonist for internal calcium channel

[Ca++]i rises

Multiple effects through Ca++-binding proteins

Diacylglycerol

Hydrophobic

Targets PKC (a kinase)

PKC requires Ca++ and DAG

Mimicked by phorbol esters (tumorogenic)

Phospholipase C as Effector
ip 3 dag signaling path
IP3/DAG Signaling Path

PKC

E

G

R

Substrate-P

substrate

IP3 & DAG

PI

Ca++

calciosome

why 2 nd messengers
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
signals and effects
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!)
signal amplification
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 it’s a kinase
  • Bottom line: one molecule of extracellular ligand generates many modified proteins inside the cell ( a large signal)
review
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
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