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Levels of Cell Regulation
• Intracellular– Within the individual cells
• Local Environment– Cells response to its immediate environment, including
presence of other cells• Locally acting factors from cells• Extracelular Matrix
• Systemic Regulation– Provides for integration of activities of cells distant from each
other• Endocrine system• Nervous system• Considerable overlap between these.
Intracellular Regulation
Substrate
Product
Enzyme
RegulatoryEnzyme
Covalent modificationCan be positive or negativephosphorylation is common.
Phosphatase
Reverses regulatoryenzyme effects
Product 2
Enzyme 2
Non-covalentModifiers
TGF- Receptor Signaling
Receptor
Hormone
ActivationDimerization
PO4
ATP
ADP
PO4
TyrosinePhosphorylation
SignalingMoleculeAssociation
PO4
PO4ATP
ADP
SubstratePhosphorylation
Downstream SignalsCan include activationof transcription factors
PgE2 Signaling
ReceptorAdenylate Cyclase
R R
C C
G Protein
Inactive Inactive
Inactive
Protein Kinase A
(PKA)
R = Regulatory Subunit
C = Catalytic Subunit
GDP
PgE2 Receptor Activation
ReceptorAdenylate Cyclase
G
GG
PKA-R
PKA-RPKA-CPKA-C
GTP
GTP
GDP
ATP
cAMP
cAMP
cAMP
Phosphorlation of substratesAltered enzyme activities
PgE2
PgE2 Receptor Inactivation
ReceptorAdenylate Cyclase
G
GG
PKA-R
PKA-R
PKA-C
PKA-C
GDP
PgE2
cAMP
G
AMP
Phosphosphatase
G has GTPaseActivity
A Few More Local Factors
Growth Factor Produced
IGF-IInsulin-like growth factor I
Epithelium and StromaAs well as liver, in blood.
Inhibitors
TGF-Transforming growth factor beta
Epithelium
IGF-BPsIGF Binding proteins (many)
Epithelium (some in stroma)
SecreteBasementMembrane
Secrete Extracellular Components
Growth Factors
Matrix Metaloprotease Secretion degrade basement membrane
Hormone Inactivation
Protease
Degradation
Degraded Hormone
Active Hormone
Inactive Hormone
Binding Protein Interaction
Binding Protein
Receptor Downregulation
SignalsSignals
Signals
Internalized Receptors
Receptor
Hormone
xxxx
xx
DegradationInternalization
Modification
often de-phosphorylation
Hormone• Chemical substance
– There are many diverse substances• Produced in one organ
– Many (all?) organs produce hormones• Transported via blood
– Now recognize other pathways too• To a distant organ
– May not be very far• Where it modifies its function
– Many different functions can be regulated by hormones
Hormone ChemistrySteroids
EstrogensProgesteroneTestosteroneAldosteroneGlucocorticoids
ProteinsInsulinGlucagonGrowth HormoneProlactinACTHOxytocinCalcitoninParathyroid hormoneMost Growth Factors
GlycoproteinsLHFSHTSHPlacntal Lactogen
Binding Equilibrium
H + R HR
Noncovalent interaction.
In equilibrium when forward and reverse rates =.
Equilibrium calculations similar to general chemistry.
Kd = concentration when 1/2 receptors occupied.
ED50 = concentration when half-maximum responses reached. NOT necessarily = Kd.
Hormone Binding
0
20
40
60
80
100
120
0.01 0.1 1 10 100 1000
[Hormone] (arbritrary)
Horm
on
e B
ou
nd
(A
rbri
trary
Un
its)
Kd(50% receptors occupied)
0
20
40
60
80
100
120
0.01 0.1 1 10 100 1000
[Hormone] (arbritrary)
Resp
on
se
(Arb
ritr
ary
Un
its)
Hormone Response
ED50(Half-Maximum Response)
Feedback
Higher Brain
Hypothalamus
AnteriorPituitary
Thyroid
Environment
TSH
Thyroxine Body Metabolism
TRF
Neural Impulses Positive
Negative
Other Inhibitory Mechanisms
• Hormone Degradation– Most hormones are degraded with a half-life of
1-30 minutes• Time for 1/2 of hormone to be degraded
• Receptor Down-regulation– Decreases response to hormone
• Stimulation of inhibitor production– Hormone can increase production of a factor
that inhibits its production or action• Ex: mammary growth factors increase production of
growth inhibitors as a feedback loop.