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PHYS 612,
ENDOCRINOLOGY:
INTRODUCTION
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SYLLABUS
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Homeostasis:
• Regulatory
Systems
– Nervous
– Endocrine
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What Endocrine
System Does
• Homeostasis
– i.e., Water & Electrolytes
•
•
•
•
•
Growth
Energy/Metabolism
Reproduction
Defense
Direct vs Indirect/Permissive
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Definitions:
•
•
•
•
•
Endocrine:
Exocrine:
Hormone:
Paracrine Factor:
Autocrine Factor:
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Types of Hormones:
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Water Soluble (Polar):
• Peptides
– Ex: Antidiuretic Hormone (ADH)
• Proteins
– Ex: Growth Hormone (GH)
• Amino Acid
– Ex: Epinephrine
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Lipid Soluble (NonPolar):
• Steroids
– Ex: Cortisol
• Amino Acid
– Ex: Thyroid Hormone, Thyroxine (T4)
• Eicosanoids
– Ex: Prostaglandins, Thromboxanes,
Leukotrienes
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Mechanism of Hormone
Action:
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HORMONE ACTION
• Take out a piece of
paper and answer
the following
question.
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How does a cell in the
adrenal cortex know to
respond to
adrenocorticotrophic
hormone (ACTH)?
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Receptors:
• Specificity:
• Affinity:
• KD = Half-Saturation
• Capacity:
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Receptors:
• LIGAND
• AGONIST
• ANTAGONIST
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Water Soluble
Hormones:
• Membrane Protein:
• Second Messenger:
• Up/Down Regulation of Proteins
Already Present:
– Primarily by Phosphorylation/
Dephosphorylation
• Gene Regulation (Secondary)
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Receptor Types:
• Serpentine
• Single Transmembrane
– Ex. Insulin Receptor
• Cytokine (Growth
Hormone/Prolactin)
• Guanylyl Cyclase-Linked
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Second Messenger
Systems:
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Second Messengers Used
by Serpentine Receptors
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Cyclic-AMP:
• Ligand binds to Receptor
• Receptor linked to
Adenylcyclase by
G-protein
• Increase production of
cAMP
• Activation of A-Kinase
• Phosphorylate protein
• Activate/Inhibit Enzymes
• Activate Transcription
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Phosphoinositol:
• Ligand Binds to Receptor
• G-protein linked to
phospholipase C (PLC)
• PLC breaks
polyphosphotidylinositol
into diacylglycerol (DAG)
and inositol triphosphate
(IP3)
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Phosphoinositol:
• IP3 Stimulates Release of
Ca++ from ER
• Ca++ Then:
– Stimulates Secretion
– Muscle Contraction
– Binds to Calmodulin
• Ca-Calmodulin Activate
CaM-Kinase
• DAG Activates C-Kinase
– Some forms of C-Kinase
Require Ca++ as a Cofactor
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Phosphoinositol:
• Kinases (C-Kinase &
CaM-Kinase
– Phosphorylate Protein
– Phosphorylate
Transcription Activating
Factors
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Second Messengers Used
by Receptors with a
Single Transmembrane
Domain
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Calcium-Calmodulin
• Cytoplasmic Ca ++
Increased
– Receptor Linked to a Ca++
Channel in Membrane
• Ca ++ Binds to Calmodulin
• Ca-Calmodulin Activates
CaM-Kinase
• CaM-Kinase
– Phosphorylates Protein
– Phosphorylates
Transcription Factors
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Cyclic-GMP:
• Membrane Bound Guanylyl
Cyclase
– Ligand Binds to Receptor
– Receptor Coupled to Guanylyl
Cyclase
– Increase Intracellular
cyclic-GMP
– Activate G-Kinase
– Phosphorylate Proteins
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Cyclic-GMP:
• Soluble Guanylyl Cyclase
– Ligand Binds to Receptor
– Receptor Opens Ca++
Channel
– Increased Intracellular Ca++
– Ca++ Activates NO-Synthase
–  NO Activates Soluble
Guanylyl Cyclase
– Increase Intracellular
cyclic-GMP
– Activate G-Kinase
– Phosphorylate Proteins
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Tyrosine Kinase
• Ligand Binds to Receptor
• Receptor Contains a Tyrosine
Kinase
• Kinase Activated
• Kinase Phosphorylates
Protein
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CYTOKINE RECEPTOR
• Ligand Binds to 2-Receptors
• Each Receptor then Binds
with a Cytoplasmic Protein
(JAK-2)
• JAK-2 is a Tyrosine Kinase
• Binding to Receptor
Activates JAK-2
• JAK-2 Then Phosphorylates
Proteins
• Ex. GH & PRL Receptors
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Membrane Receptor
Degradation
• Receptor-Mediated
Endocytosis
– Clathrin Coated Pits
– Endocytosis
– Lysosomal
Digestion of Ligand
– Receptors Returned
to Membrane
Surface
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LIPID SOLUBLE
HORMONE RECEPTORS
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Cytoplasmic/Nuclear
Receptors
• Ligand binds to
receptor
• Hormone-receptor
complex attaches to
another hormonereceptor complex
• Dimer then binds to
DNA.
• Stimulate or inhibit
mRNA production
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Cytoplasmic/Nuclear
Receptors (Cont.)
• Hormone-receptor
complex binds
cofactors
• Cofactors modify
action of hormonereceptor complex
on mRNA
production
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Membrane Receptor
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Review Steroid/Thyroid
Hormone Receptors
• Cytoplasmic/Nuclear
Receptors
– Ligand binds
– Dimer & move to
nucleus
– Modulate mRNA
production
• Membrane Receptors
– Second Messenger
CONTROL OF
ENDOCRINE SECRETION
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Negative Feedback
• Maintains level near a set point
– Results in small oscillations about the
set point
– Ex: Thermostat/Heater
– Ex: Blood Glucose
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NEGATIVE FEEDBACK
PANCREAS
BLOOD
GLUCOSE
GLUCAGON
LIVER
TIME
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NEGATIVE FEEDBACK
PANCREAS
BLOOD
GLUCOSE
GLUCAGON
LIVER
TIME
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NEGATIVE FEEDBACK
PANCREAS
BLOOD
GLUCOSE
GLUCAGON
LIVER
TIME
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NEGATIVE FEEDBACK
PANCREAS
BLOOD
GLUCOSE
GLUCAGON
LIVER
TIME
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NEGATIVE FEEDBACK
PANCREAS
BLOOD
GLUCOSE
GLUCAGON
LIVER
TIME
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NEGATIVE FEEDBACK
PANCREAS
BLOOD
GLUCOSE
GLUCAGON
LIVER
TIME
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NEGATIVE FEEDBACK
PANCREAS
BLOOD
GLUCOSE
GLUCAGON
LIVER
TIME
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NEGATIVE FEEDBACK
PANCREAS
BLOOD
GLUCOSE
GLUCAGON
LIVER
TIME
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NEGATIVE FEEDBACK
PANCREAS
BLOOD
GLUCOSE
GLUCAGON
LIVER
TIME
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NEGATIVE FEEDBACK
PANCREAS
BLOOD
GLUCOSE
GLUCAGON
LIVER
TIME
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Positive Feedback
• Rare Because It Results in a
“Runaway” Condition
– Dam Breaking
• Serves to Signal a Specific Event
– Ovulation
• Serves to Signal the Continuation of
a Process
– Lactation
• Must Have A Brake!!!
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POSITIVE FEEDBACK
PITUITARY
GLAND
E2
LH
LH
OVARY
TIME
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POSITIVE FEEDBACK
PITUITARY
GLAND
E2
LH
LH
OVARY
TIME
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POSITIVE FEEDBACK
PITUITARY
GLAND
E2
LH
LH
OVARY
TIME
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POSITIVE FEEDBACK
PITUITARY
GLAND
LH
LH
E2
OVARY
TIME
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POSITIVE FEEDBACK
PITUITARY
GLAND
LH
LH
E2
OVARY
TIME
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POSITIVE FEEDBACK
PITUITARY
GLAND
E2
LH
LH
OVARY
TIME
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Factors Affecting a
Hormone’s Plasma
Concentration
•
•
•
•
Secretion
Transport
Metabolism
Excretion
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Secretion:
• Pulsatile Secretion
• Tonic vs Episodic
• Rhythms
– Ultradian
– Circadian
– Monthly
– Seasonal
– Developmental
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Transport
• Polar/Water soluble:
• Non-Polar/Lipid Soluble
– Transport Proteins
• Ex: Thyroid Binding Globulin
– Non-Specific Protein Binding
• Ex: Albumin
– Free Hormone Levels
• What Counts is the Amount of
Hormone Available to the Cell
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Metabolism
• Liver
• Other
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Excretion
• Kidney
• Feces
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Endocrinopathies
•
•
•
•
Hypersecretion
Hyposecretion
Receptor Down-regulation/Inactivity
Decreased Target Organ Conversion
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