BIOL 1080 Lecture Notes - Lecture 6: Secretion, Lipophilicity, Chronic Obstructive Pulmonary Disease
2 May 2018
School
Department
Course
Professor
*goal: to change overall profile of cellular protein/enzymatic
activity
Binds to cytosolic or nuclear receptors
•
Turns on genes to make new proteins (i.e. enzymes)
•
Lipid-soluble (lipophillic) chemical messengers
Binds to cell surface (plasma membrane) receptor
•
Directly, or through second messengers, alters the
activity of existing enzymes/proteins
•
Water-soluble (hydrophilic) chemical messengers
Note: second messengers could still affect gene expression and
protein production
Cells may express many different types of receptors
•
There may be 100's or 1000's of a given receptor on a
cell surface (=amplification)
•
Amount of receptor is controllable (can be up or down
regulated)
•
Response is based on receptor activity:
Response of a cell to a given messenger can be tissue
specific based on the type of receptor
•
In heart muscles, causes potassium efflux
and relaxation
!
Agonists could be used to treat hypertension
in COPD
!
Muscarinic:
○
In skeletal muscle, causes sodium influx and
contraction
!
Nicotinic receptor antagonists can be used
as muscle relaxants
!
Nicotinic:
○
Ex. Neurotransmitter acetylcholine has two general
classes of receptors:
•
Receptor Specificity:
Properties of Chemical Messengers:
Lipophobic/Hydrophilic
Messenger
Lipophilic/Hydr
ophobic
Messenger
Chemical
Classes
Amino acids, amines,
peptides
Steroids,
eicosanoids,
thyroid
hormones
Storage in
Secretory
Cell
Secretory vesicles None
Mechanism
of Secretion
Exocytosis Diffusion
Transport in
Blood
Dissolved Bound to carrier
protein
Location of
Receptor
Plasma Membrane Cytosol or
nucleus
Signal
transduction
mechnism
Open/close ion channels,
activate membrane-bound
enzymes, G proteins and
second messenger systems
Alter
transcription of
mRNA (alter
protein
synthesis)
Relative time
to onset of
response
Fast Slow
Relative
duration of
response
Short Long
Relative half
life
Short Long
After binding to nuclear receptor, forms
hormone/receptor complex
•
This complex can cause many mRNA to be formed in
the nucleus (from Hormone Response Element aka
HRE)
•
mRNA are transported into the cytosol and ribosomes
form many proteins from each mRNA
•
Signal Transduction and Amplification -Liphophilic
Messengers
*see slide
○
Second messenger: cAMP
○
Kinase phosphorylates a target and usually
uses ATP as the phosphate donor
!
Note: ensuing cascade activation on one protein
(Kinase A) activates another
○
Ex. G proteins (gluanosine)
•
Channel-linked receptors (neurotransmitters)
○
Other second messengers (Ca2+, cGMP)
○
Can also include:
•
Signal Transduction -Hydrophilic Messengers
One messenger molecule leads to phosphorylation of
millions of proteins
•
One messenger binds to one receptor
○
Several G proteins are activated
○
Each G protein activates an adenylate cyclase
○
Each adenylate cyclase generates hundreds of
cAMP molecules
○
Or is degraded by phosphodiesterase (to
turn signal off)
!
Each cAMP activates a protein kinase A
○
Each protein kinase A phosphorylates hundreds of
proteins
○
Steps:
•
Signal Amplification -Hydrophilic Messenger
*see slide
•
Epinephrine (messenger)
•
Increase in cAMP formation
•
Activation of protein kinase A
•
Activation of hormone sensitive lipase
•
Activation of lipolysis and release of fatty acids
•
Ex. Signalling Cascade during Exercise (hydrophilic
messenger)
Multiple tissues are affected by numerous hormones
during exercise
•
Eprinephrine, norepinephrine and glucagon
increase cAMP
○
Insulin decreases cAMP (one of the only
hormones to decrease during exercise)
○
Several hormones use cAMP as a second messenger:
•
Heart muscle -increase strength of contraction
and heart rate
○
Skeletal -facilitate glycogenolysis and lipolysis
○
Adipose -stimulate lipolysis
○
Liver -stimulate glycogenolysis and
gluconeogenesis
○
Consequence of cAMP activation in various target
tissues:
•
Signal Transduction During Exercise:
Maintaining normal fluid levels in the lumen is a matter
of chloride and sodium secretion
•
Too much loss of fluid (diarrhea) can be life-threatening
•
Cl-and Na+ pumps are regulated by a protein kinase
•
*see slide
•
Cholera grows under the mucus layer in the small
intestine
○
The secreted cholera toxin activates G protein for
a prolonged period (doesn't shut off signal)
○
Causes efflux of Cl-, Na+ and water (20L/day)
○
Consequence: life-threatening diarrhea
○
Cholera toxin and life threatening diarrhea:
•
Signaling from a Disease Perspective -Fluid Secretion into the
Intestinal Lumen
In 30,000 americans
○
1/25 people of European descent carry one gene
for CF (heterozygotes)
○
CFTR is a Cl-transporter
!
CF characterized by a homozygous mutation in
the CFTR gene
○
Impairs regulation of sweat, digestive juices and
mucus (i.e. thicker secretions, less water loss)
○
Could protect against the severe loss of fluid that
occurs due to the cholera toxin
○
Cystic Fibrosis:
•
Cystic Fibrosis Transmembrane Conductance Regulator
(CFTR)
Treat muscle wasting
!
A new drug for body builders/strength
athelets
!
Myostatin inhibitors:
○
*see slide
○
Ex. Myostatin -acts as an inhibitor of muscle protein
synthesis
•
Some water-soluble ligands can influence the nucleus (i.e.
gene expression)
Chemical Signal Transduction
Monday,)October)23,)2017
11:10)AM
*goal: to change overall profile of cellular protein/enzymatic
activity
Binds to cytosolic or nuclear receptors
•
Turns on genes to make new proteins (i.e. enzymes)
•
Lipid-soluble (lipophillic) chemical messengers
Binds to cell surface (plasma membrane) receptor
•
Directly, or through second messengers, alters the
activity of existing enzymes/proteins
•
Water-soluble (hydrophilic) chemical messengers
Note: second messengers could still affect gene expression and
protein production
Cells may express many different types of receptors
•
There may be 100's or 1000's of a given receptor on a
cell surface (=amplification)
•
Amount of receptor is controllable (can be up or down
regulated)
•
Response is based on receptor activity:
Response of a cell to a given messenger can be tissue
specific based on the type of receptor
•
In heart muscles, causes potassium efflux
and relaxation
!
Agonists could be used to treat hypertension
in COPD
!
Muscarinic:
○
In skeletal muscle, causes sodium influx and
contraction
!
Nicotinic receptor antagonists can be used
as muscle relaxants
!
Nicotinic:
○
Ex. Neurotransmitter acetylcholine has two general
classes of receptors:
•
Receptor Specificity:
Properties of Chemical Messengers:
Lipophobic/Hydrophilic
Messenger
Lipophilic/Hydr
ophobic
Messenger
Chemical
Classes
Amino acids, amines,
peptides
Steroids,
eicosanoids,
thyroid
hormones
Storage in
Secretory
Cell
Secretory vesicles
None
Mechanism
of Secretion
Exocytosis
Diffusion
Transport in
Blood
Dissolved
Bound to carrier
protein
Location of
Receptor
Plasma Membrane
Cytosol or
nucleus
Signal
transduction
mechnism
Open/close ion channels,
activate membrane-bound
enzymes, G proteins and
second messenger systems
Alter
transcription of
mRNA (alter
protein
synthesis)
Relative time
to onset of
response
Fast
Slow
Relative
duration of
response
Short
Long
Relative half
life
Short
Long
After binding to nuclear receptor, forms
hormone/receptor complex
•
This complex can cause many mRNA to be formed in
the nucleus (from Hormone Response Element aka
HRE)
•
mRNA are transported into the cytosol and ribosomes
form many proteins from each mRNA
•
Signal Transduction and Amplification -Liphophilic
Messengers
*see slide
○
Second messenger: cAMP
○
Kinase phosphorylates a target and usually
uses ATP as the phosphate donor
!
Note: ensuing cascade activation on one protein
(Kinase A) activates another
○
Ex. G proteins (gluanosine)
•
Channel-linked receptors (neurotransmitters)
○
Other second messengers (Ca2+, cGMP)
○
Can also include:
•
Signal Transduction -Hydrophilic Messengers
One messenger molecule leads to phosphorylation of
millions of proteins
•
One messenger binds to one receptor
○
Several G proteins are activated
○
Each G protein activates an adenylate cyclase
○
Each adenylate cyclase generates hundreds of
cAMP molecules
○
Or is degraded by phosphodiesterase (to
turn signal off)
!
Each cAMP activates a protein kinase A
○
Each protein kinase A phosphorylates hundreds of
proteins
○
Steps:
•
Signal Amplification -Hydrophilic Messenger
*see slide
•
Epinephrine (messenger)
•
Increase in cAMP formation
•
Activation of protein kinase A
•
Activation of hormone sensitive lipase
•
Activation of lipolysis and release of fatty acids
•
Ex. Signalling Cascade during Exercise (hydrophilic
messenger)
Multiple tissues are affected by numerous hormones
during exercise
•
Eprinephrine, norepinephrine and glucagon
increase cAMP
○
Insulin decreases cAMP (one of the only
hormones to decrease during exercise)
○
Several hormones use cAMP as a second messenger:
•
Heart muscle -increase strength of contraction
and heart rate
○
Skeletal -facilitate glycogenolysis and lipolysis
○
Adipose -stimulate lipolysis
○
Liver -stimulate glycogenolysis and
gluconeogenesis
○
Consequence of cAMP activation in various target
tissues:
•
Signal Transduction During Exercise:
Maintaining normal fluid levels in the lumen is a matter
of chloride and sodium secretion
•
Too much loss of fluid (diarrhea) can be life-threatening
•
Cl-and Na+ pumps are regulated by a protein kinase
•
*see slide
•
Cholera grows under the mucus layer in the small
intestine
○
The secreted cholera toxin activates G protein for
a prolonged period (doesn't shut off signal)
○
Causes efflux of Cl-, Na+ and water (20L/day)
○
Consequence: life-threatening diarrhea
○
Cholera toxin and life threatening diarrhea:
•
Signaling from a Disease Perspective -Fluid Secretion into the
Intestinal Lumen
In 30,000 americans
○
1/25 people of European descent carry one gene
for CF (heterozygotes)
○
CFTR is a Cl-transporter
!
CF characterized by a homozygous mutation in
the CFTR gene
○
Impairs regulation of sweat, digestive juices and
mucus (i.e. thicker secretions, less water loss)
○
Could protect against the severe loss of fluid that
occurs due to the cholera toxin
○
Cystic Fibrosis:
•
Cystic Fibrosis Transmembrane Conductance Regulator
(CFTR)
Treat muscle wasting
!
A new drug for body builders/strength
athelets
!
Myostatin inhibitors:
○
*see slide
○
Ex. Myostatin -acts as an inhibitor of muscle protein
synthesis
•
Some water-soluble ligands can influence the nucleus (i.e.
gene expression)
Chemical Signal Transduction
Monday,)October)23,)2017 11:10)AM
Document Summary
*goal: to change overall profile of cellular protein/enzymatic activity. Turns on genes to make new proteins (i. e. enzymes) Directly, or through second messengers, alters the activity of existing enzymes/proteins. Note: second messengers could still affect gene expression and protein production. Cells may express many different types of receptors. There may be 100"s or 1000"s of a given receptor on a cell surface (=amplification) Amount of receptor is controllable (can be up or down regulated) Response of a cell to a given messenger can be tissue specific based on the type of receptor. Neurotransmitter acetylcholine has two general classes of receptors: In heart muscles, causes potassium efflux and relaxation. Agonists could be used to treat hypertension in copd. In skeletal muscle, causes sodium influx and contraction. Nicotinic receptor antagonists can be used as muscle relaxants. Open/close ion channels, activate membrane-bound enzymes, g proteins and second messenger systems. After binding to nuclear receptor, forms hormone/receptor complex.
