signal-transduction pathways · „ no men is an island entire of itself; every man is a piece of...
TRANSCRIPT
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Signal-Transduction Pathways
Copyright © 2007 by W. H. Freeman and CompanyPal Bauer 2014/2015
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„ No men is an island entire of itself; every man
Is a piece of the continent, a part of the main”
John Donne
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Introduction
• Cells must respond adequately to external
stimuli to survive.
• Cells respond to stimuli via cell signaling.
• Some signal molecules enter cells; others
bind to cell-surface receptors.
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Quorum sensing in bacteria
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The slime mould
Dictyostelium Discoideum
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The Basic Elements of Cell
Signaling Systems
• Extracellular messenger molecules
transmit messages between cells.
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In autocrine signaling, the cell has receptors on its surface that respond
to the messenger
Interleukine-1, FAS-L, TNF-alfa etc.
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During paracrine signaling, messenger molecules travel short distances
through extracellular space.
Somatostatine, histamine, prostaglandins, quorum sensing etc.
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During endocrine signaling, messenger molecules reach their target cells
through the bloodstream.
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Connexin gap junctions; ATP, GSH
Anoikis, integrins, selectins, syndecans,cadherins etc.
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Chemical
Synapse -
Signal
Transduction
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Extracellular vesicles, exosomes, microvesicles
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Reception
Transduction
Response
Binding of epinephrine to G protein-coupled receptor (1 molecule)
Inactive G protein
Active G protein (102 molecules)
Inactive adenylyl cyclase
Active adenylyl cyclase (102)
ATP
Cyclic AMP (104)
Inactive protein kinase A
Active protein kinase A (104)
Inactive phosphorylase kinase
Active phosphorylase kinase (105)
Inactive glycogen phosphorylase
Active glycogen phosphorylase (106)
Glycogen
Glucose 1-phosphate(108 molecules)
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Direct Ligand Binding Plot and the Derived Scatchard Plot
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Biological Activity and Receptor
Occupancy• 50% of maximum biological
activity with ~18% of receptors occupied
• >80% of maximum biological activity with 50% of receptors occupied
• Epinephrine levels of ~10-10
M can stimulate glucogenolysis in liver cells, despite its relatively low binding affinity (Kd ~ 10-5 M)
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I. The Basic Elements of Cell
Signaling Systems
• Receptors on or in target cells receive the
message.
– Some cell surface receptors generate an
intracellular second messenger through an
enzyme called an effector.
– Other surface receptors recruit proteins to
their intracellular domains.
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Overview of
signaling
pathways
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• Signaling pathways consist of a series
of proteins.
– Each protein in a pathway alters the
conformation of the next protein.
– Protein conformation is usually altered by
phosphorylation.
– Target proteins ultimately receive a message
to alter cell activity.
– This overall process is called signal
transduction.
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A signal transduction pathway
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A Survey of Extracellular
Messengers and Their Receptors
• Extracellular messengers include:
– Small molecules such as amino acids and
their derivatives (glutamate, acetylcholine,
adrenaline, dopamine, TSH).
– Gases such as NO and CO
– Steroids
– Eicosanoids, which are lipids derived from
fatty (arachidonic) acids.
– Various peptides and proteins
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• Receptor types include:
– G-protein coupled receptors (GPCRs)
– Receptor protein-tyrosine kinases (RTKs)
– Ligand gated channels
– Steroid hormone receptors
– Specific receptors such as B-and T-cell
receptors
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I. G Protein-Coupled Receptors
and Their Second Messengers
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Signaling with G-Protein
Coupled ReceptorsReceptors (GPCRs)• integral membrane proteins with 7 transmembrane segments
• binding site for diverse ligands (hormones, odorants, tastants, light)
• >907 human GPCRs (384 olfactory receptors)
G Proteins• trimeric complexes of a, b and g subunits (20 Ga, 5 Gb, 12 Gg)
• Ga is GTPase switch protein (GDP off / GTP on)
• attached to membrane: Ga is acylated: Gg is prenylated
Effectors• adenylate cyclase, phospholipase C, phosphodiesterase, channels
• control levels of secondary messengers (cAMP, cGMP, DAG, IP3)
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A GPCR and a G protein
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Lipid Rafts and Signal
Transduction• microdomains on surface of
plasma membrane
• segregate proteins based on attached lipid
– acylated proteins in raft
– prenylated proteins not
• caveolin causes inward curvature forming caveolae
• localized in lipid rafts / caveolae:
– G-protein coupled receptors
– Tyr kinase receptors (some)
• not in lipid rafts:
– Ras and Gg subunit (prenylated)
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Fluorescent Proteins
• Structure of green
fluorescent protein (GFP)
from jellyfish
• Chromophore is
autocatalytically formed by
cyclizing and oxidizing
SYG sequence
• Site directed mutagenesis
of GFP produced variety
of other fluorescent
proteins of different
wavelengths
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Assay for Measuring Protein
Interactions• Fluorescence Resonance Energy
Transfer (FRET) uses emission of one chromophore as excitation for a second chromophore
• If proteins interact excitation of 1st
chromophore gives emission of 2nd
• Applied to signal transduction study
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Mechanism of receptor-
mediated
activation/inhibition by G
proteins
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G Protein-Coupled Receptors and
Their Second Messengers
• Signal Transduction by G Protein-Coupled Receptors
– Ligand binding on the extracellular domain changes the intracellular domain.
– Affinity for G proteins increases, and the receptor binds a G protein intracellularly.
– GDP is exchanged for GTP on the G protein, activating the G protein.
– One ligand-bound receptor can activate many G proteins.
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G Protein-Coupled Receptors and
Their Second Messengers
• Termination of the Response
– Desensitization – by blocking active receptors
from turning on additional G proteins.
– G protein-coupled receptor kinase (GRK)
modifies GPCR via phosphorylation.
– Proteins called arrestins compete with G
proteins to bind GPCRs.
– Termination of the response is accelerated by
regulators of G protein signaling (RGSs).
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G Proteins and Effector ProteinsGas activator cAMP
Gai inhibitor cAMP
Gaq phosphoinositides
G12/13 unknown
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Second Messengers
*ER = endoplasmic reticulum; IP3 = inositol 1,4,5-trisphosphate;
PLC = phospholipase C; PI = phosphatidyl inositol;
DAG = diacylglycerol; PLD = phospholipase D.
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G Protein-Coupled Receptors and
Their Second Messengers
• Second Messengers – cyclic AMP
– The Discovery of Cyclic AMP
• It is a second messenger, which is released into
the cytoplasm after binding of a ligand.
• Second messengers amplify the response to a
single extracellular ligand.
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Formation of cAMP from ATP
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Images of cAMP Transients in Cultured Aplysia Sensory Neurons.
The cell was loaded with a fluorophore that would allow for the quantification of
cAMP concentrations within the cell.
A: Free cAMP in the resting cell is < 5 X 10-8 M.
B: Stimulation with serotonin, activates adenylate cyclase increasing cytoplasmic
cAMP to ~ 1 X 10-6 M (red), especially within fine processes with a high
surface to volume ratio. Thus, within 20 sec of stimulation, the intracellular
[cAMP] increased ~ 20-fold.
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The variety of processes that can be
affected by changes in [cAMP]
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G Protein-Coupled Receptors and
Their Second Messengers
• Other Aspects of cAMP Signal
Transduction Pathways
– Some PKA molecules phosphorylate nuclear
proteins.
– Phosphorylated transcription factors regulate
gene expression.
– Phosphatases halt the reaction cascade.
– cAMP is produced as long as the external
stimulus is present.
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Examples of hormone-induced responses
mediated by cAMP
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PKA-anchoring protein signaling
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G Protein-Coupled Receptors and
Their Second Messengers
• Phosphatidylinositol-Derived Second
Messengers
– Some phospholipids of cell membranes are
converted into second messengers by
activated phospholipases.
• Phosphatidylinositol Phosphorylation
– Phosphoinositides (PI) are derivatives of
phosphatodylinositol.
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Phosphatidylinositides in Signal
Transduction
Ptdlns
ATP ADP
PI-4KPtdlns4P
ATP ADP
PIP-5KPtdlns(4,5)P2
ATP
ADP
PI-3KPTEN
Pi
Ptdlns(4,3,5)P3
DAG Ins(1,4,5)P3
PLC
(PIP2)
(PIP3)
[Ca2+] ↑PKC(Active)
PKB (Active)
PI-3 Kinase Pathway
(IP3)
IP3/DAG Pathway
Activation of
Protein Kinase C
Activation of
Protein Kinase B
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Cellular responses elicited by adding IP3
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Phospholipid-based second messengers
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G Protein-Coupled Receptors and
Their Second Messengers
• Phosphatidylinositol-specific phospholipase C-bproduces second messengers (IP3) and diacylglycerol (DAG) derived from phosphatidylinositol-inositol triphosphate
• DAG activates protein kinase C, which phosphorylates serine and threonine residues on target proteins.
• The phosphorylated phosphoinositides form protein-binding domains, which are connected to the PH domains of participating proteins
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IP3-Mediated Signal Transduction
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Examples of responses mediated by
Protein Kinase C
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The Role of Calcium as an
Intracellular Messenger• Cytoplasmic calcium levels are determined
by events within a membrane.
– Calcium levels are low in the cytosol (100
nM) because it is pumped out into the
extracellular space and the membrane is
highly impermeable to the ion.
– Calcium channels can be transiently opened
by action potential or calcium itself (1 mM).
– Calcium binds to calcium-binding proteins
(such as calmodulin), which affects other
proteins.
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Regulation of Cytosolic [Ca2+]
• IP3-gated channels in ER release Ca2+ into cytosol
• cytosolic [Ca2+] lowers affinity of gated channels for IP3
• causes oscillation in cytosolic [Ca2+]
• cytosolic [Ca2+] measured using fluorescent Ca2+-binding dye
• Time course of cytosolic [Ca2+] with α1-adrenergic receptor stimulation by epinephrine
• high sustained Ca2+ release may be toxic
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Experimental demonstration of localized
release of intracellular Ca2+
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Calcium wave in a starfish egg
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Calcium-induced calcium release
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Examples of mammalian proteins
activated by Ca2+
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Calmodulin
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II: Protein-Tyrosine Phosphorylation
as a Mechanism for Signal
Transduction
• Protein-tyrosine kinases phosphorylate
tyrosine residues on target proteins.
• Protein-tyrosine kinases regulate cell
growth, division, differentiation, survival,
and migration.
• Receptor protein-tyrosine kinases
(RTKs) are cell surface receptors of the
protein-tyrosine kinase family.
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2) Receptor tyrosine kinase (RTK) family of receptors
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Protein-Tyrosine Phosphorylation as a
Mechanism for Signal Transduction
• Receptor Dimerization
– Results from ligand binding.
– Protein kinase activity is activated.
• Tyrosine kinase phosphorylates another subunit of
the receptor (autophosphorylation).
• RTKs phosphorylate tyrosines within
phosphotyrosine motifs.
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Activation of Protein Tyrosine
Kinases• Activation of a Tyr kinase by phosphorylation
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Steps in the
activation of
RTK
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Protein-Tyrosine Phosphorylation as a
Mechanism for Signal Transduction
• Phosphotyrosine-Dependent Protein-Protein Interactions
– Phosphorylated tyrosines bind effector proteins that have SH2 domains and PTB domains.
– SH2 and PTB domain proteins include:• Adaptor proteins that bind other proteins.
• Docking proteins that supply receptors with other tyrosine phosphorylation sites.
• Signaling enzymes (kinases) that lead to changes in cell.
• Transcription factors
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A diversity of signaling proteins
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Protein-Tyrosine Phosphorylation as a
Mechanism for Signal Transduction
• The Ras-MAP Kinase Pathway
– Ras is a G protein embedded in the
membrane by a lipid group.
– Ras is active when bound to GTP and inactive
when bound to GDP.
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The structure of a G protein and the
G protein cycle
GDI-guanine dissociation inhibitorinhibitor; GEF-guanine
exchange factor; GAP- GTP-ase activator protein
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Protein-Tyrosine Phosphorylation as a
Mechanism for Signal Transduction
• Ras-MAP kinase pathway
– Accessory proteins play a role:
• GTPase-activating proteins (GAPs) shorten the
active time of Ras.
• Guanine nucleotide-exchange factors (GEFs)
stimulate the exchange of GDP for GTP.
• Guanine nucleotide-dissociation inhibitors
(GDIs) inhibit release of GDP.
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Protein-Tyrosine Phosphorylation as a
Mechanism for Signal Transduction
• Ras-MAP kinase pathway (continued)
– The Ras-MAP kinase cascade is a cascade
of enzymes resulting in activation of
transcription factors.
– Adapting the MAP kinase to transmit different
types of information:
• End result differs in different cells/situations.
• Specificity of the MAP kinase response due to
differences in the types of kinases participating
and differences in spatial organization of
components.
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The steps of a
generalized MAP
kinase cascade
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Mammalian Ras activation
GRB2
PP
PP
PLC
PI3K
SH2 Domain
GAP
(DRK)
SOS
RasGTP
Downstream
pathways
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GRB2
PP
PP
PLC
PI3K
GAP
Ca2+ signaling can be activated by RTKs via PLC g
Ca2+ signaling
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GRB2
PP
PP
PLC
PI3K
GAP
Other signaling pathways
Cell survival
RTKs can activate PI3-Kinase
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GRB2
PP
PP
PLC
PI3K
Src
Cell proliferation,
Gene expression, …
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Protein-Tyrosine Phosphorylation as a
Mechanism for Signal Transduction.
• Signaling by the Insulin Receptor
– Insulin regulates blood glucose levels by
increasing cellular uptake of glucose.
– The insulin receptor is a protein-tyrosine
kinase
• Autophosphorylated receptor associates with
insulin receptor substrate proteins (IRSs).
• IRSs bind proteins with SH2 domains, which
activate downstream signal molecules.
• SH2 domain-containing proteins are kinases that
phosphorylate a lipid, PI 3-kinase (PI3K).
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The role of tyrosine-phosphorylated IRS in
activating a variety of signaling pathways
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Protein-Tyrosine Phosphorylation as a
Mechanism for Signal Transduction
• Glucose Transport
– PKB regulates glucose uptake by GLUT4
transporters.
• GLUT4 transporters reside in intracellular
membrane vesicles.
• Vesicles fuse with the membrane in response to
ligand binding to the IR.
– Diabetes mellitus is caused by defects in
insulin signaling and Type 2 diabetes is
caused by gradual insensitivity to insulin.
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Regulation of glucose uptake in muscle
and fat cells by insulin
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Convergence, Divergence and Crosstalk
Among Different Signaling Pathways
• Signaling pathways can converge ,
diverge, and crosstalk as follows:
– Signals form unrelated receptors can
converge to activate a common effector.
– Identical signals can diverge to activate a
variety of effectors.
– Signals can be passed back and forth
between pathways as a result of crosstalk.
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Examples of convergence, divergence, and
crosstalk among signal transduction
pathways
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Convergence, Divergence and Crosstalk
Among Different Signaling Pathways
• Convergence – GPCRs, receptor tyrosine
kinases, and integrins bind to different
ligands but they all can lead to a docking
site for Gbr2.
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Convergence of signals transmitted from a
GPCR, an integrin, and receptor tyrosine
kinase
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Convergence, Divergence and Crosstalk
Among Different Signaling Pathways (3)
• Divergence – all of the examples of signal
transduction so far are evidence of
divergence of how a single stimulus sends
signals along a variety of different
pathways.
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Convergence, Divergence and Crosstalk
Among Different Signaling Pathways (4)
• Crosstalk – more and more crosstalk is
found between signaling pathways:
– cAMP can block signals transmitted through
the MAP kinase cascade.
– Ca2+ and cAMP can influence each other’s
pathways.
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An example of crosstalk between
two major signaling pathways
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Intracellular Signaling Pathways activated by RTKs and GPCRs
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Two Stages of Amplification
Adenylyl cyclase activity is modulated by the interplay
of stimulatory and inhibitory G proteins.
Hormone binding to β1- and α2-receptors activates
adenylyl cyclase, whereas hormone binding to α2-
receptors leads to inhibition of adenylyl cyclase.
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The Role of NO as an
Intracellular Pathway• Nitric oxide (NO) is both an extracellular
and intercellular messenger with a variety
of functions.
• NO is produced by nitric oxide synthase.
– NO stimulates guanylyl cyclase, making
cGMP.
– cGMP decreases cytosolic calcium and
relaxes smooth muscle.
– NO also plays a role in male arousal.
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Signal transduction by means of NO and
cGMP
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Steroid Hormones: Features
• Cholesterol-derived
– Lipophilic and can enter target cell
• Cytoplasmic or nuclear receptors
(mostly)
• Activate DNA for protein synthesis
• Slower acting, longer half-life
• Examples
– Cortisol, estrogen, and testosterone
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Steroid Hormones: Structure
Figure 7-6
Cholesterol is the parent compound for all steroid hormones.
modified by enzymes to make
steroid hormones such as
Estradiol (an estrogen)Aldosterone
Adrenal
cortex
Ovary
Cortisol
In ovaryIn adrenal cortex
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Steroid Hormones: Action
Figure 7-7
1
Cell
membrane
Interstitial
fluid
Cytoplasmic
receptor
Endoplasmic
reticulum
Nucleus
Nuclear
receptor
DNA
Translation
Cell surface receptor
Rapid responses
Transcription
produces mRNA
Steroid
hormone
Blood
vessel
Protein
carrier
New
proteins
Steroid hormone receptors are in the
cytoplasm or nucleus.
Most hydrophobic steroids are bound to
plasma protein carriers. Only unbound
hormones can diffuse into the target cell.
Translation produces new proteins
for cell processes.
Some steroid hormones also bind to
membrane receptors that use second
messenger systems to create rapid
cellular responses.
The receptor-hormone complex binds to
DNA and activates or represses one or
more genes.
Activated genes create new mRNA that
moves back to the cytoplasm.
2a
2
5
4
3
1
2a
2
3
4
5
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Steroid Receptor Structure
This superfamily of ligand-activated transcription factors is also structurally related.
Three well conserved regions:
-Hormone binding domains (HBD) in carboxyl terminus
-DNA-binding domain (DBD) 5’ to ligand binding domain
A nonconserved hypervariable region, which may contribute to transcriptional activity of receptor
DBD HBDhypervariable
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Not All Intracellular Receptors are
Associated with HSPs.
HSPs bind to glucocorticoid, mineralocorticoid,
androgen, progesterone, and estrogen receptors
in absence of hormone.
However, receptors for thyroid hormone, retinoic
acid, and vitamin D are not bound to HSPs.
This second group of receptors is bound to their
hormone response element (HRE) on 5’flanking
region of target genes, but are inactive until
hormone binds to them.
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Following hormone binding, intracellular
receptors act as transcription factors,
binding to hormone response elements
(HREs) on the 5’ flanking region of target
genes.
HRE target gene
5’ flanking region
Steroid Receptors bind to Hormone
Response Elements (HREs) on DNA
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Steroid Receptors bind to Hormone
Response Elements (HREs) on DNA
Hormone
Progesterone,
Androgen,
Glucocorticoid,
Mineralocorticoid
Consensus HREs
AGAACAnnnTGTTCT
Estrogen
Thyroid hormone
Retinoids
Vitamin D
AGGTCAnnnTGACCT
AGGTCATGACCT
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Palindromic Sequences Allow
Binding of Receptors as Dimers
5’ -AGAACAnnnTGTTCT- 3’
H HNNN
A T
C G
A T
A T
G C
A TTATA EXON 1…...
Transcription
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Ligand gated ion channels
Gated by ligands present outside of the
cell
In fact they are receptors
All of them are nonselective cation
channels
Mediate effects of neurotransmitters
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GPCRs that Regulate Ion Channels: Muscarinic Acetylcholine Receptor
The neurotransmitter, acetylcholine (ACH) binds to two types of receptors known as the nicotinic and muscarinic acetylcholine receptors. The nicotinic receptor is itself a ligand-gated ion channel that opens on ACH binding. This receptor is located in the neuromuscular junctions of striated muscle. The muscarinic ACH receptor, is a GPCR found in cardiac muscle cells that is coupled to an inhibitory G proteinThe binding of ACH to this receptor triggers dissociation of Gai-
GTP from Gßg, which in this case, directly binds to and opens a K+
channel. The movement of K+ down its concentration gradient to the outside of the cell, increases the positive charge outside the membrane, hyperpolarizing the cell. This results in the slowing of heart rate.
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Acetylcholine Receptor
b
a
ACh
g (or e)
dACh
consists of a pentamer of
protein subunits, with two
binding sites for
acetylcholine, which,
when bound, alter the
receptor's configuration
and cause an internal
pore to open.
This pore allows Na+ ions
to flow down their
electrochemical gradient
into the cell.
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Nicotinic Acetylcholine Receptor
A ligand gated ion channel
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the resting (closed) ion channel to acetylcholine (ACh)
produces the excited (open) state. Longer exposure leads to
desensitization and channel closure.
Acetylcholine
binding sites
ACh
Na+, Ca2+ Continued
excitation
Desensitized
(gate closed)Excited
(gate open)
Resting
(gate closed)
Outside
Inside
ACh