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Lecture 22 Signal Transduction 1. Important Concepts in Signal Transduction. Primary messengers Membrane receptors Second messengers Amplification Signal termination 7TM receptors G proteins Adenylate cyclase - Protein Kinase A Phospholipase C- Protein Kinase C, Ca 2+ Channels.

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important concepts in signal transduction
Important Concepts in Signal Transduction
  • Primary messengers
  • Membrane receptors
  • Second messengers
  • Amplification
  • Signal termination
  • 7TM receptors
  • G proteins
  • Adenylate cyclase - Protein Kinase A
  • Phospholipase C- Protein Kinase C, Ca2+ Channels
slide4

The term signal transduction refers to the biochemical mechanism responsible for “transmitting” extracellular signals inside the cell, which ultimately lead to the activation of target proteins that control metabolic pathways or regulate gene expression.

Courtesy: Roger Miesfeld

steps of signal transduction
Steps of Signal Transduction

1. Signal molecule (primary messenger, first messenger, ligand) travels to the cell.

2. Primary messenger binds to the extracellular domain of a receptor protein and initiates a structural change in the receptor which is propagated across the membrane.

  • Membrane receptors sense the stimulus and transfer info across the membrane.
  • Exception: some molecules, for example steroid hormones, move across membranes, bind to proteins and act, generally at the nucleus.
  • Most molecules are too polar or too large to cross the membrane, so the stimulus does not enter without membrane receptors.
  • Generally, receptors are intrinsic (integral) membrane proteins with extra- and intracellular domains.
steps of signal transduction1
Steps of Signal Transduction

3. Receptor protein stimulates signaling proteins

4. Second messengersamplify the signal

  • Free to diffuse
  • Cross talk between pathways exists

5. Second messengers bind to additional signaling proteins

6. Signal is propagated, often by a protein kinase cascade

steps of signal transduction2
Steps of Signal Transduction

7. Target proteins are affected (activated, inhibited)

  • Transcription factors
  • Metabolic enzymes
  • Cytoskeletal proteins
  • Transport proteins
  • Etc.

8. Signal is terminated

  • Phosphatases
the biochemical basis for signal transduction involves three primary mechanisms
The biochemical basis for signal transduction involves three primary mechanisms:

1) protein conformational changes

2) covalent protein modifications

3) altered rates of gene expression

slide9

First/primary messengers are small diffusible biomolecules.

These can be produced through endocrine mechanisms and act at a distance.

Or they can function locally as paracrine or autocrine signals.

Courtesy: Roger Miesfeld

small molecules act as diffusible signals
Small molecules act as diffusible signals

First/Primary Messengers

Human growth hormone and insulin are peptide hormones

Cortisol is a steroid that is derived from cholesterol

Epinephrine, also known as adrenaline, is a derived from the amino acid tyrosine

Acetylcholine is a neurotransmitter that binds the acetylcholine receptor

NO is produced by deamination of L-arginine

small molecules act as diffusible signals1
Small molecules act as diffusible signals

Second Messengers

Second messengers amplify the receptor-generated signal

Fine tuning

Rapid production of maximum response

one of the best characterized second messengers is cyclic amp camp
One of the best characterized second messengers is cyclic AMP (cAMP).

Produced by the enzyme adenylate cyclase from ATP.

Receptor activation of adenylate (adenylyl) cyclase generates large amounts of cAMP, which in turn, binds to and activates downstream signaling proteins such as cAMP dependent protein kinase A (PKA). Importantly, the intracellular concentration of cAMP is carefully controlled by the relative levels of receptor-activated adenylate cyclase and soluble forms of cAMP phosphodiesterase (PDE) which converts cAMP to AMP.

Courtesy: Roger Miesfeld

slide13

The intracellular concentration of cAMP is carefully controlled

Relative levels of receptor-activated adenylate cyclase and soluble forms of cAMP phosphodiesterase (PDE) which converts cAMP to AMP.

Courtesy: Roger Miesfeld

another second messenger important in signal transduction is cyclic gmp cgmp
Another second messenger important in signal transduction is cyclic GMP (cGMP)

Produced from GTP by the enzyme guanylyl cyclase. The cGMP analog Sildenafil, also know as Viagra, is used to treat sexual dysfunction by inhibiting the activity of cGMP phosphodiesterase (PDE). The molecular structure of sildenafil is similar to cGMP and binds tightly to cGMP PDE.

Courtesy: Roger Miesfeld

slide15

The Kissing Bug, Rhodnius prolixus, delivers NO to their victims by injecting heme-containing proteins called nitrophorins that carry NO into the wound along with their saliva.

Courtesy: Roger Miesfeld

slide16
Some Other Second Messengers: diacylglycerol (DAG), inositol 1,4,5-trisphosphate (IP3) and calcium ion (Ca2+).

Intracellular levels of DAG, IP3 and Ca2+ are controlled by the activity of a membrane associated enzyme called phospholipase C (PLC).

Receptor-mediated activation of phospholipase C leads to cleavage of the membrane phospholipid phosphatidylinositol 4,5-bisphosphate (PIP2) to form DAG and IP3.

Courtesy: Roger Miesfeld

slide17

The term signal transduction refers to the biochemical mechanism responsible for “transmitting” extracellular signals inside the cell, which ultimately lead to the activation of target proteins that control metabolic pathways or regulate gene expression.

Courtesy: Roger Miesfeld

slide18

5 Major classes of receptor proteins:

the gatekeepers of the cell

Courtesy: Roger Miesfeld

slide19

Seven-Transmembrane-Helix Receptors (7TM receptors)

All seven-transmembrane-helix receptors are coupled to G Proteins :

G Protein Coupled Receptors or GPCRs

Fig. 14-4

adrenergic receptor signal transduction pathway
β-Adrenergic receptor signal transduction pathway

Binding of ligand on the extracellular domain of the β- adrenergic receptor causes a structural change on the cytoplasmic side

This structural change causes a change in an associated signal-coupling protein called a G-protein (guanyl nucleotide binding protein)

The change in the G-protein involves GDP vs. GTP binding affinity.

The G-protein activates adenylate cyclase, increasing cAMP levels

inactive form of g protein heterotrimer binds gdp
Inactive form of G protein heterotrimer binds GDP

Notice the three different subunits here

g protein activation
G Protein Activation

Receptor conformational change causes structural change in the G protein –

GDP leaves, GTP binds

GTP binding cause a structural change in the G protein—molecular switch

βγ dimer then dissociates and activated α subunit goes off to affect other proteins

slide24
The human genome contains 15 α, 5 β and 10 γ subunits, leading to many different possible combinations (~1000) and functions
the activated g subunit binds to other proteins to activate them
The activated Gα subunit binds to other proteins to activate them

Gαs binds to adenylate cyclase, activating it, leading to increased levels of cAMP, which turns on Protein Kinase A.

Fig. 14-7

slide27

Glycogen is a storage form of glucose.

Glycogen is broken down to glucose when the body needs energy.

Glucose levels in the blood are tightly controlled.

Glycogen synthesis (anabolism) and degradation (catabolism) are highly regulated by hormone signaling.

The liver is one of two major storage depots for glycogen, which in response to epinephrine or glucagon signaling, provides an important source of glucose for export throughout the body when dietary glucose is limiting.

Epinephrine is the fight or flight hormone.

Glucagon is released by the pancreas and has been called the hunger hormone because it signals low blood glucose levels.

slide29

Switch II, undergoes a conformational change in the presence of GTP and is critical for stimulation of adenylate cyclase activity

activation of phospholipase c
Activation of phospholipase C

Human liver cells contain α1 adrenergic receptors

bind epinephrine and signal glycogen degradation through a second messenger pathway linked to a phosphorylation cascade.

α1 adrenergic receptors are coupled to a heterotrimeric G protein containing Gαq

activates the enzyme phospholipase C (PLC) through a mechanism very similar to Gαs stimulation of adenylate cyclase activity

Phospholipase C is a membrane associated protein

catalyzes the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) to form the second messengers DAG and IP3.

function of second messengers ip3 dag
Function of second messengers IP3 & DAG
  • IP3 binds to calcium channels on the endoplasmic reticulum
    • causes a rapid increase in intracellular Ca2+ levels.
  • Released Ca2+ binds to protein kinase C (PKC)
    • stimulates its association with DAG at the plasma membrane resulting in activation of the PKC kinase function
  • Ca2+ binds to calmodulin, activating:
    • phosphorylase kinase
    • calmodulin dependent kinase
  • PKC and calmodulin dependent kinase
    • phosphorylate and inactivate glycogen synthase
  • Calmodulin-activated phosphorylase kinase stimulates glycogen degradation by activating glycogen phosphorylase
g proteins reset themselves
G proteins reset themselves

Possesses GTPase activity

The βγ dimer then re-associates with the α subunit, preventing it from further propagating the signal

Ready to start all over again.

Fig. 14-9

summary of g protein coupled receptor signaling
Summary of G protein coupled receptor signaling

1. Receptor-mediated activation of GDP-GTP exchange in Gα subunits.2. Gα stimulation of an effector enzyme that generates 2nd messengers.3. Activation of a phosphorylation cascade by 2nd messenger signaling.4. Inactivation of Gα by effector stimulation of the intrinsic GTPase activity.5. Signal duration is controlled by loss of 2nd messengers and receptor desensitization.

what happens when receptors aren t reset
What happens when receptors aren’t reset?

Dopamine receptor and cocaine / amphetamines

Opiate receptor and heroin

Serotonin 5-HT1A receptor and MDMA (Ecstasy)

These are all G protein coupled receptors (GPCRs)!

First you get high, then you become addicted.

Why? Because the dopamine D2 receptor and the opiate and the 5-HT1A receptors bind these drugs much more tightly than they do their natural ligands. They don’t get reset properly, the whole signaling cascade downstream is “messed up”.

After exposure, more receptor is needed to get the “normal” physiological response. The body responds by altering gene expression and receptor levels in the brain.

One exposure to MDMA or Meth permanently alters brain function! There is no going back. This is a huge social problem right now.