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 fac
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
Signaling within cells
NTs
1. Ion channel – binding of the S to the R
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 S 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
-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)
d) RTKs
3. Tyrosine-linked and RTKs – binding
of the S 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
Growth
phosphate group)
Factors
-the way the RTK and the TLK activate
their targets are different but the end
effect is the same
Hormones: Mechanisms of Signaling
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hormone producing cell = endocrine cell
– e.g. thyroid, pituitary
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Autocrine signaling
– cell responds to the hormone it produces
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Paracrine signaling
– local action
– local hormone (paracrine hormones)
act on neighboring cells
– autocrines act on same cell that secreted
them
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Endocrine signaling
– circulating hormones (endocrine
hormones)
– act on distant targets
– travel in blood
Types of Hormones
• water-soluble
• lipid -soluble
Lipid-soluble Hormones
• Steroids
– lipids derived from cholesterol
– made in SER
– different functional groups attached to
core of structure provide uniqueness
testosterone
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
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 the PM 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
• 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
insulin
• 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
• peptide 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__mech
anism_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
Action of Water-Soluble Hormones
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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 a series of proteins in the cytosol
called kinases
– kinases act to phosphorylate their targets – either
activating them or inhibiting them
– this speeds up/slows down physiological responses
within the cell
– phosphodiesterase inactivates cAMP quickly
many second messengers are made in cells in response
to specific hormones
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e.g. calcium, IP3, DAG
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
• 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
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
• 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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cAMP Second Messenger systems
best studied system: binding of epinephrine to the b2-adrenergic receptor
activates the Gs protein and produces cAMP
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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 permit multienzyme
regulation and 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
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bind to protein/peptide classes
of hormones
– e.g. insulin
– e.g. growth factors – EGF,
NGF, bFGF, PDGF
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H binding leads to
dimerization of the RTK and
activation of the kinase
activity endogenous to the
receptor
this activity phosphorylates its
target and initiates the
downstream signaling cascade
major initiating protein is
called Ras (GTPase)
activation of the RTK leads to
binding of the GTP-bound
form of Ras
this activated Ras than
activates multiple downsteam
paths
the major one is called the
MAPK pathway
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