04/21/23 SCNM, PHYS 612, Introduction 1

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 (Non-Polar):

• 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:

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 ActivateCaM-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

Second Messengers Used by Receptors with a

Single Transmembrane Domain

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23

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

27

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

LIPID SOLUBLE HORMONE RECEPTORS

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Cytoplasmic/Nuclear Receptors

• Ligand binds to receptor

• Hormone-receptor complex attaches to another hormone-receptor complex

• Dimer then binds to DNA.

• Stimulate or inhibit mRNA production

Cytoplasmic/Nuclear Receptors (Cont.)

• Hormone-receptor complex binds cofactors

• Cofactors modify action of hormone-receptor 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

LIVER

GLUCOSE

TIME

GLUCAGON BLOODGLUCOSE

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NEGATIVE FEEDBACK

PANCREAS

LIVER

GLUCOSE

TIME

GLUCAGON BLOODGLUCOSE

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NEGATIVE FEEDBACK

PANCREAS

LIVER

GLUCOSE

TIME

GLUCAGON BLOODGLUCOSE

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NEGATIVE FEEDBACK

PANCREAS

LIVER

GLUCOSE

TIME

GLUCAGON BLOODGLUCOSE

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NEGATIVE FEEDBACK

PANCREAS

LIVER

GLUCOSE

TIME

GLUCAGON BLOODGLUCOSE

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NEGATIVE FEEDBACK

PANCREAS

LIVER

GLUCOSE

TIME

GLUCAGON BLOODGLUCOSE

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NEGATIVE FEEDBACK

PANCREAS

LIVER

GLUCOSE

TIME

GLUCAGON BLOODGLUCOSE

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NEGATIVE FEEDBACK

PANCREAS

LIVER

GLUCOSE

TIME

GLUCAGON BLOODGLUCOSE

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NEGATIVE FEEDBACK

PANCREAS

LIVER

GLUCOSE

TIME

GLUCAGON BLOODGLUCOSE

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NEGATIVE FEEDBACK

PANCREAS

LIVER

GLUCOSE

TIME

GLUCAGON BLOODGLUCOSE

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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 FEEDBACKLH

TIME

PITUITARYGLAND

OVARY

LH E2

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POSITIVE FEEDBACKLH

TIME

PITUITARYGLAND

OVARY

LH E2

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POSITIVE FEEDBACKLH

TIME

PITUITARYGLAND

OVARY

LH E2

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POSITIVE FEEDBACKLH

TIME

PITUITARYGLAND

OVARY

LHE2

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POSITIVE FEEDBACKLH

TIME

PITUITARYGLAND

OVARY

LH

E2

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POSITIVE FEEDBACKLH

TIME

PITUITARYGLAND

OVARY

LH E2

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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