Transcript No Slide Title

Cell Communication: Hormones, Growth factors
and Neurotransmitters
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cells can communicate with those
right next to them or can
communicate with targets at a
distance
communication can be through
direct contact = adhesion-based
mechanisms, transfer of materials
through gap junctions
or through the production of
extracellular factors called signals
- e.g. hormones,
neurotransmitters, neuropeptides,
growth factors
this is called extracellular signaling
these compounds exert their
effects by binding to the target
cells and/or entering the cell
the ultimate goal is to affect the
function of the cell
– through modifying the expression
of genes/proteins
-6 steps to extracellular signaling
1.
synthesis of signal (hormone, NT)
2.
release of signal (exocytosis)
3.
transport of signal to target (local? distance?)
4.
detection of signal by target (binding to receptors)
5.
change in target cell function
6. removal of the signal & loss of effect
-three types of extracellular
chemical messengers:
1. paracrines (e.g. growth factors)
2. neurotransmitters
3. hormones
Extracellular Signaling:
Mechanisms
hormones
hormones, NTs, growth factors
growth
factors growth factors
Hormones,
Extracellular Signaling: Mechanisms
• most signals produced by cells within the body bind to
receptors that are specific for that signal
• most receptors are found on the cell surface
• although some can be found within the cell!
• binding of the signal (ligand) to the receptor results in a
series of events (signal transduction) within the cell that
changes the cells function
– e.g. may change the transcription rate of a gene – effects protein
production
NTs
1. Ion channel – binding of the signal (ligand) to the receptor
changes the conformation of the R and allows transit of a specific
ion
-this allows entry of the signaling ion
-responsible for the changing of membrane potentials
-once the signal is removed the “gate” closes
HORMONES
NTs
2. GPCR – binding of the signal (S) to its R activates the R
-the R binds to an adjacent plasma membrane protein = adenylyl cyclase (AC)
(adenylate cyclase)
-AC then converts ATP to cAMP (cyclic AMP)
-cAMP acts as a signal within the cell = second messenger – effects cell activity
-BUT some G proteins can inhibit this pathway!!!! (no AC activation, no cAMP
production)
5 players in this mechanism:
1.
Hormone
2.
Receptor = GPCR
3.
G protein (stimulatory or inhibitory)
4.
Effector – adenylate cyclase, PLC
5.
Second messanger = cAMP, calcium
3. Tyrosine-linked and RTKs – binding
of the signal to the R causes the R to
dimerize (pair-up)
-this activates a target (kinase)
-this kinase then goes on to activate its
target by phosphorylating it (adding a
phosphate group)
-the way the RTK and the TLK activate
their targets are different but the end
effect is the same
d) RTKs
Growth
Factors
KINASE = protein that phosphorylates a
Target
-binds and breaks down ATP into
ADP + Pi
-takes this Pi and attaches it to its
target
-most of the time the target is
another kinase
-this kinase phosphorylates its
target = kinase cascade
Hormones: Mechanisms of Signaling
• hormone producing cell =
endocrine cell
• can use three mechanisms
• Autocrine signaling
– cell responds to the hormone it
produces
• Paracrine signaling
– local action
– local hormone (paracrine
hormones)
act on neighboring cells
– autocrines act on same cell that
secreted them
• Endocrine signaling
– circulating hormones (endocrine
hormones)
– act on distant targets
– travel in blood
Types of Hormones
• water-soluble
• lipid -soluble
Lipid-soluble Hormones
• Steroids
testosterone
– lipids derived from cholesterol
– made in SER
– different functional groups attached to
core of structure provide uniqueness
aldosterone
• e.g. cortisol, progesterone, estrogen,
testosterone, aldosterone
• Thyroid hormones
cortisol
– tyrosine ring plus attached iodines
– are lipid-soluble
• Retinoic acid
– lipids derived from retinol (vitamin A)
– regulate proliferation, differentiation
and death of many cell types
• some vitamins can acts a lipid-soluble
hormones
– e.g. vitamin D
• Nitric oxide (NO)
- gas
Lipid-soluble Hormones
• Eicosanoids
– prostaglandins or leukotrienes
– derived from arachidonic acid (fatty
acid)
– AA is converted either into
prostaglandin H or into the
leukotrienes
– conversion of AA into
prostaglandins is regulated by the
COX enzymes
– both act in the inflammatory
reaction
• e.g. stimulate smooth muscle cells
to contract
• e.g. stimulate nerve cells – pain
Aspirin
Ibuprofen
Phospholipids or
Diacylglycerol
PGH synthase
-Cox-1 OR Cox-2
+ peroxidase
PGH3
HPETE
Leukotriene A
Leukotriene C4
PGI
PGD
Thromboxane
(platelets)
Leukotriene D4
PGE
Leukotriene E4
PGF
-COX-1 isoform is for the normal production of prostaglandins
-COX-2 isoform is produced by inflammatory cells
-aspirin – prevents the binding of arachadonic acid to the PGH synthase
catalytic site
-ibuprofen – directly binds to the active site – acts a a competitor to AA
-SC-558 class drugs (e.g. Vioxx) – specifically inhibit the activity of the COX-2 isoform
Lipid-soluble Hormones
• synthesis of steroid hormones from cholesterol backbone
requires a series of specific enzymatic reactions that
modifies the cholesterol
– these enzymes are specific for each steroid made
– they are located in specific cell types
• e.g. enzymes for cortisol are located specifically in the adrenal cortex
• not stored – once formed they released by diffusion
through into the blood
– carrier proteins can be specific or some can pick up any steroid
hormone
• e.g. serum albumin – indiscriminate in its steroid
• the hormone becomes active once released
• therefore the body keeps a balance of bound-inactive steroid
hormones and unbound hormones that rapidly enter the cell
• 50% of the water soluble catecholamines are actually bound to
albumin – reason is unclear
• only cholesterol is stored in the cytoplasm
Water-soluble Hormones
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insulin
Amine, peptide and protein hormones
– modified amino acids to protein chains
– serotonin, melatonin, histamine,
epinephrine, insulin, dopamine
– protein hormones – comprised of one or
many polypeptide chains
• insulin, glucagon
– peptide hormones – comprised of chains
of amino acids
• e.g. growth hormone, oxytocin
– amine hormones – derived from the
amino acids tyrosine or tryptophan
• epinephrine (tyrosine and
phenylalanine), serotonin
(tryptophan), dopamine (tyrosine)
• one subcategory is called the:
– catecholamines: epinephrine,
norepi.
and dopamine
– can also act as neurotransmitters
Water-soluble Hormones
• water-soluble hormones are synthesized and secreted
using the same mechanism that regulates the secretion
of any other protein
– made as precursors in the ER – called preprohormones
– transport to the Golgi where they are “pruned” to give rise to
the active hormone
– packaged and secreted from the Golgi
– stored in the cytoplasm until needed
– secretion is triggered only by specific stimulus
Action of Lipid-Soluble Hormones: Endogenous signaling
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Hormone must be carried by a
transport protein that allows it to
dissolve within the aqueous (watery)
environment of the blood plasma
Hormone diffuses through phospholipid
bilayer & into cell
the receptor is located within the cell
(cytoplasm or the nucleus)
binding of H to R results in its
translocation into the nucleus
the H then binds directly to specific
sequences within the DNA = response
elements
this binding turns on/off specific genes
– activates or inhibits gene transcription
if turned on - new mRNA is formed &
directs synthesis of new proteins
new protein alters cell’s activity
if turned off – no new protein results
and the cell’s activity is altered
Action of Lipid-Soluble Hormones
– For an animation: http://highered.mcgrawhill.com/sites/0072943696/student_view0/chapter10/animation__mec
hanism_of_steroid_hormone_action__quiz_1_.html
Action of Lipid-Soluble Hormones
• some lipid-soluble hormone don’t cross the
plasma membrane – too large
• therefore they bind with receptors on the
cell surface and trigger signaling events
within the cells
– signal similar to water-soluble hormones
– e.g. prostaglandins and leukotrienes
Action of Water-Soluble Hormones
• easily travels through the blood hydrophilic
• but cannot diffuse through plasma
membrane!
• therefore absolutely requires the
expression of receptors on the cell surface
– integral membrane proteins that act as
first messenger
• the receptor protein activates a series of
signaling events within the cells
– e.g. epinephrine binds to receptor and
activates an adjacent G-protein in
membrane
– G-protein activates adenylate cyclase
to convert ATP to cyclic AMP (cAMP)
in the cytosol
– cAMP acts as a 2nd messenger
– cAMP activates its target =
kinase
– kinases act to phosphorylate
their targets
– physiological response occurs
within the cell
– phosphodiesterase
inactivates cAMP quickly
• Cell response is turned off unless
new hormone molecules arrive
• this mechanism allows for
amplification – one H-R
combination can activate two G
proteins which activates 4
kinases which activate 16 more
kinases etc…….
Action of Water-Soluble Hormones
-animations: go to you tube and search
“G protein animation”
OR
-http://highered.mcgrawhill.com/sites/0072943696/student_view0/c
hapter10/animation__second_messenger__
camp.html
Action of Water-Soluble Hormones
• so the binding of a hormone to a receptor results
in downstream cellular events
• either through direct activity of the receptor
(activated by the ligand) or through production of
a second messenger
– types:
• 1. cAMP: produced by adenylyl cyclase/AC (activated by
hormone G protein interaction)
• 2. calcium
– -IP3 & DAG
• cell expresses numerous type of G proteins
that interact with the GPCRs
– some activate adenylyl cyclase and stimulate
production of cAMP – Gs (G stimulatory)
– others inhibit AC – Gi (G inhibitory
Gs protein
Adenylyl cyclase
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best studied system: binding of epinephrine to the b2-adrenergic receptor
activates the Gs protein and produces cAMP
cAMP
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Second Messenger
systems
Gs protein is comprised of three subunits
the active subunit is the alpha subunit
however the beta and gamma subunits have signaling roles also
note the Gsa subunit cycles between GTP and GDP bound states – called a GTPase protein
the cycling between GTP and GDP helps control its function
– ANIMATION: http://www.youtube.com/watch?v=NMeBZlbs2dU
cAMP Second Messenger systems
• the ability to bind and hydrolyze GTP determine the function of the
Gsa subunit
• also the site at which bacterial toxins can affect this signaling path
• the hydrolysis of the GTP on the Gsa protein is catalysed by the Gsa
protein itself
• cholera stimulates the
addition of an ADP onto
the Gsa protein (takes it
from intracellular NAD+)
cAMP Second Messenger systems
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the activity of AC is modified also by interactions with the Gi protein
therefore the cell can modify its level of cAMP made by stimulating the GPCRs that
activate either Gs or Gi proteins
the alpha subunit of the Gi protein (Gia) also interacts with AC (at a different location)
this Gia protein is also an GTPase and requires the binding of GTP to become active and
inhibit AC – once GTP is hydrolyzed the protein dissociates the AC inhibition is relieved
– this is the basis of pertussis – the pertussis toxin prevents the hydrolysis of GTP bound to the
Gia – leads to prolonged inhibition of AC and drops in intracellular cAMP levels – inhibits cell
signaling
cAMP Second Messenger systems
• cAMP phosphorylates a class of kinases called cAMPdependent protein kinases (PKAs)
• the cell has multiple isoforms of PKAs
• the PKA then phosphorylates another downstream
kinase as its target
• these kinases can vary from cell type to cell type and
also vary according to the upstream ligand
– epinephrine binding activates PKA - activates GPK (glycogen
phophorylase kinase)
– insulin activates PKA which then activates acetyl CoA
carboxylase and then pyruvate dehydrogenase
Kinase cascades amplify hormone signals
IP3 and DAG – calcium second
messengers
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most intracellular calcium stores are
sequestered in the ER or other vesicles
RTK or GPCR pathways trigger the
activation of phospholipase C in the PM
– e.g. hormone-GPCR binding triggers
activation of a Gq protein which then
activates phospholipase C
results in production of IP3 and DAG
– IP3 diffuses through the cytoplasm
and activates Ca channels within the
PM or within the ER to release or
allow entry of calcium within the
cytoplasm
– increased cytoplasmic calcium
activates a class of calcium-dependent
kinases called PKCs (protein kinase C)
– role for DAG in this step
http://bcs.whfreeman.com/lodish5e/content/cat_010/1301001.htm?v=chapter&i=13010.01&s=13000&n=00010&o
Phosphorylation
of substrates
Water soluble hormones and RTKs
• bind to protein/peptide
classes of hormones and
growth factors
• signal binding leads to
dimerization of the RTK
• this activates the RTK
• Activated RTK binds and
activates several “adaptor
proteins”
• Adaptor proteins job is to
activate Ras (GTPase)
• this activated Ras than
activates multiple downsteam
paths
• the major one is called the
MAPK pathway
Growth factors
Peptide hormones
Water-soluble Hormone Signaling:
Mechanisms
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hormones can utilize more than
one receptor and more than one
pathway to activate the same
target
– e.g. can bind and activate both
GPCRs and RTKs
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provides the body with flexibility
in its choice of hormone
also allows two hormones to
combine to increase the strength
of an event
or allows one hormone to
decrease the cells response while
the other hormone is trying to
increase it
Interference with Normal Cell-Signaling
Pathways
• Mutations in the ras proto-oncogene and p53 tumorsuppressor gene are common in human cancers
• Mutations in the ras gene can lead to production of a
hyperactive Ras protein and increased cell division
© 2011 Pearson Education, Inc.
Figure 18.24
MUTATION
1 Growth
factor
Ras
3 G protein
GTP
Ras
P
P
P
P
P
P
2 Protein kinases
Hyperactive Ras protein
(product of oncogene)
issues signals on its
own.
GTP
MUTATION
3 Active
form
of p53
UV
light
2 Receptor 4 Protein kinases
(phosphorylation
cascade)
1 DNA damage
in genome
Defective or missing
transcription factor,
such as
p53, cannot
activate
transcription.
DNA
NUCLEUS
5 Transcription
factor (activator)
Protein that
inhibits
the cell cycle
DNA
Gene expression
(b) Cell cycle–inhibiting pathway
Protein that
stimulates
the cell cycle
EFFECTS OF MUTATIONS
Protein
overexpressed
Protein absent
(a) Cell cycle–stimulating pathway
Cell cycle
overstimulated
(c) Effects of mutations
Increased cell
division
Cell cycle not
inhibited