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Second Messengers and Signal Transduction






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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
Second Messengers and Signal Transduction

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Slide 1

Second Messengers and Signal Transduction

Tim Bloom, Ph.D.

104A Hall of Science

893-1712

Slide 2

Overview

  • Signal transduction- a concept

  • Second messengers

    • Characteristics

    • Examples

    • Benefits

Slide 3

Signal Transduction

  • Intracellular communication

    • Detection of extracellular event

    • Generation of internal change

  • Bottom line- presence of external ligand causes a change inside cell

Slide 4

Ligands

Estrogen

Acetylcholine

Insulin

Epinephrine

Receptors

Transcription factor

Sodium channel

Receptor kinase

G protein-coupled receptor

Signaling Examples

Slide 5

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)

Slide 6

Second Messengers

  • General characteristics

    • Low amounts in resting state

    • Regulated synthesis

    • Regulated destruction

    • Act through other proteins

Slide 7

Second Messengers

  • Cyclic nucleotides

    • cAMP

    • cGMP

  • Calcium

  • Lipid derivatives

    • IP3

    • DAG

    • Many others

Slide 8

Cyclic AMP

  • Made from ATP

  • Adenylate cyclase

    • Membrane effector

    • Needs a G-protein

  • Hydrolysis of cAMP to AMP terminates signal

Slide 9

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.

Slide 10

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

Slide 11

cAMP Signaling Path

E

Gs

R

cAMP

ATP

Slide 12

cAMP Signaling Path

E

Gs

R

cAMP

+

ATP

PKA

Slide 13

PDE

-

cAMP Signaling Path

E

Gs

R

cAMP

+

ATP

PKA

Substrate-P

substrate

Slide 14

Cyclic GMP

  • Made from GTP

  • Guanylate cyclase

    • Membrane or soluble

    • Acts as receptor

    • No G-protein involved

  • Hydrolysis of cGMP to GMP terminates signal

Slide 15

cGMP

  • Regulates several proteins as ligand

    • Ion channels

    • Protein kinase

  • Important in smooth muscle relaxation

  • Important in visual system

Slide 16

Calcium as a 2nd Messenger

  • Low cytoplasmic Ca++ at rest

  • Channels open with voltage and/or ligands

  • Channels in PM and in “calciosome”

Slide 17

Calcium as a 2nd Messenger

  • High cytoplasmic Ca++ when stimulated

  • Pumps move calcium out of cytoplasm

  • Pumps in PM and in “calciosome”

Slide 18

Calcium as a 2nd Messenger

  • Many binding proteins mediate Ca++ action

  • Activated by calcium

    • Troponin C

    • Calmodulin

  • Calmodulin is multifunctional

Slide 19

Calmodulin

Ca++

Ca++

Ca++

Ca++

Slide 20

Calmodulin

Ca++

Ca++

Ca++

Ca++

Slide 21

Calmodulin Targets

  • Adenylate cyclase (some versions)

  • Phosphodiesterase (some versions)

  • Myosin light chain kinase

  • Calmodulin-dependent kinases

  • Calcineurin (a phosphatase)

  • And so on…

Slide 22

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

Slide 23

IP3/DAG Signaling Path

PKC

E

G

R

Substrate-P

substrate

IP3 & DAG

PI

Ca++

calciosome

Slide 24

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

Slide 25

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!)

Slide 26

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)

Slide 27

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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