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Cell Communication: Hormones, Growth factors
and Neurotransmitters
•
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 OR
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
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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
Cell Communication: Hormones, Growth factors
and Neurotransmitters
-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
growth factors
hormones, NTs, growth factors
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
Extracellular
Signaling:
Mechanisms
1. Ion channel – ion channel (transmembrane protein) acts as a
receptor for a signal (ligand)
- binding of the ligand to the ion channel changes the
conformation of the receptor and allows transit of a
specific ion through it
-this allows entry of the signaling ion
-responsible for the changing of membrane potentials
-once the signal is removed the channel closes
-many ion channels open and close through a portion of the
protein that acts like a “gate”
HORMONES
Neurotransmitters
2. G-protein Coupled Receptor (GPCR) – binding of the signal (S) to its Receptor
activates the R
-the R binds to and activates an adjacent plasma membrane protein = called a G protein
-the G protein effects the activity of another plasma membrane protein called an Effector
(E)
e.g. most common - adenylyl cyclase or adenylate cyclase (AC)
-Effector then creates a second message within the cell
e.g. AC 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 (1st messanger)
2. Receptor = GPCR
3.
G protein (stimulatory or inhibitory)
4.
Effector – adenylate cyclase, PLC
5.
Second messanger = cAMP, calcium
d) Receptor Tyrosine-linked Kinases = Growth factors
GF binding
Receptor dimerization
& activation
Growth
Factors
KINASE
CASCADE
Activation of kinases
3. Receptor Tyrosine-linked kinases
(RTKs)
– binding of the signal to the Receptor
causes the R to dimerize (pair-up)
-the R activates enzymes called kinases
-an activated kinase then goes on to
activate another target by
phosphorylating it (adding a phosphate
group)
KINASE = protein that phosphorylates a Target
protein
-binds and breaks down ATP into ADP + Pi
-kinase takes this Pi and attaches it to its
target
-this activates the target
-most of the time the target is another
kinase
-this second kinase phosphorylates its
target = kinase cascade results
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
– 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
– tyrosine ring plus attached iodines
• Retinoic acid
cortisol
– 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 the fatty acid called
arachidonic acid
– arachidonic acid is used as a
starting point for making either
prostaglandins or leukotrienes
– both act in the inflammatory
reaction
• e.g. stimulate smooth muscle cells
to contract
• e.g. stimulate nerve cells – pain
– conversion of arachidonic acid into
prostaglandins is regulated by the
COX enzymes
• these enzymes are targeted by antiinflammatories like aspirin, ibuprofen,
Vioxx
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
• not stored – once formed they released by diffusion through
into the blood
– require binding to a carrier protein to be transported in the blood
– carrier proteins can be specific or some can pick up any steroid hormone
• only cholesterol is stored in the cytoplasm
Water-soluble Hormones
•
insulin
Amine, peptide and protein hormones
– range from 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 and
norepinephrine(tyrosine), 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
•
•
•
•
•
•
•
Lipid-soluble hormone must be carried
by a carrier/transport protein that
allows it to dissolve within the aqueous
environment of the blood plasma
Hormone diffuses through phospholipid
bilayer & into target cell
the Receptor is located within the cell
(cytoplasm or the nucleus)
binding of H to R in the cytoplasm
results in its translocation into the
nucleus
the H then binds directly to specific
sequences within the DNA = response
elements
this binding turns on specific genes –
activates or inhibits gene transcription
new mRNA is formed & directs synthesis
of new proteins
–
new protein alters cell’s activity
Action of Lipid-Soluble Hormones
– For an animation: http://highered.mcgrawhill.com/sites/0072943696/student_view0/chapter10/animation__mechanism_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 they require the expression of
Receptors on the cell surface – integral
membrane proteins
• 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
– protein cascade results
– cAMP activates its target =
kinase
– kinases act to phosphorylate
their targets
– kinase cascade results
– 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…….
Kinase cascades amplify hormone signals
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 of second messengers:
• 1. cAMP: produced by adenylate cyclase/AC (activated by
hormone G protein interaction)
• 2. calcium
– -IP3 & DAG
G proteins
• cell expresses numerous type of G proteins that
interact with the GPCRs
– some activate adenylate cyclase and stimulate
production of cAMP – Gs (G stimulatory)
– others inhibit AC – Gi (G inhibitory)
Gs protein
Adenylate cyclase
•
•
best studied system: binding of epinephrine to the b2-adrenergic receptor
activates a Gs protein and produces cAMP
cAMP
–
–
–
–
–
Second Messenger
systems
Gs protein is comprised of three subunits – alpha, beta, gamma
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 determines 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 “locks” the Gs
alpha subunit into its
GTP-bound “ON” state
• persistent activation of
adenylate cyclase
• severe disruption of
water absorption by GI
tract
• can be fatal within hours
cAMP Second Messenger systems
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the activity of AC can be modified also by interactions with a Gi protein
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therefore the cell can modify its level of cAMP made by stimulating the GPCRs that
activate either Gs or Gi proteins
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the alpha subunit of the Gi protein (Gia) also interacts with AC (at a different location)
–
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prevents its activity – no second messenger made
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
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

different effects of cAMP in different cells is due to the
kinase cascade that PKA starts
IP3 and DAG – Calcium as a second messenger
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most intracellular calcium stores are
sequestered in the ER or other vesicles
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RTK or GPCR pathways trigger the activation
of Phospholipase C/PLC – located in the
plasma membrane
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PLC breaks down a phospholipid called PIP2
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results in production of inositol
triphosphate/IP3 and diacylglycerol/DAG
– IP3 diffuses through the cytoplasm and
activates Ca2+ channels on the ER release of calcium within the cytoplasm
– IP3 can also open these channels in the
PM and allow Ca2+ to diffuse in
– increased cytoplasmic calcium activates
a class of calcium-dependent kinases
called PKCs (protein kinase C) – role for
DAG in this step
– PKCs then activate kinase cascades
Phosphorylation
of substrates
http://bcs.whfreeman.com/lodish5e/content/cat
_010/1301001.htm?v=chapter&i=13010.01&s=13000&n=0
Water soluble hormones and RTKs
• bind to protein/peptide classes
of hormones and growth factors
• Receptor is called a receptortyrosine kinase/RTK
• signal binding leads to
dimerization of the RTK
• this activates the RTK
• activated RTK binds and
activates several “adaptor
proteins”
• adaptor protein’s job is to
activate Ras (GTPase)
• this activated Ras then activates
multiple downstream kinase
cascades
• 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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allows two hormones to combine
to increase the strength of an
event
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or allows one hormone to
decrease the cells response while
the other hormone is trying to
increase it