10/20/2015SCNM, PHYS 612, Introduction1 PHYS 612, ENDOCRINOLOGY: INTRODUCTION

10/20/2015SCNM, PHYS 612, Introduction2 SYLLABUS

10/20/2015SCNM, PHYS 612, Introduction3 Homeostasis: Regulatory Systems –Nervous –Endocrine

10/20/2015SCNM, PHYS 612, Introduction4 What Endocrine System Does Homeostasis –i.e., Water & Electrolytes Growth Energy/Metabolism Reproduction Defense Direct vs Indirect/Permissive

10/20/2015SCNM, PHYS 612, Introduction5 Definitions: Endocrine: Exocrine: Hormone: Paracrine Factor: Autocrine Factor:

10/20/2015SCNM, PHYS 612, Introduction6 Types of Hormones:

10/20/2015SCNM, PHYS 612, Introduction7 Water Soluble (Polar): Peptides –Ex: Antidiuretic Hormone (ADH) Proteins –Ex: Growth Hormone (GH) Amino Acid –Ex: Epinephrine

10/20/2015SCNM, PHYS 612, Introduction8 Lipid Soluble (Non- Polar): Steroids –Ex: Cortisol Amino Acid –Ex: Thyroid Hormone, Thyroxine (T 4 ) Eicosanoids –Ex: Prostaglandins, Thromboxanes, Leukotrienes

10/20/2015SCNM, PHYS 612, Introduction9 Mechanism of Hormone Action:

10/20/2015SCNM, PHYS 612, Introduction10 HORMONE ACTION Take out a piece of paper and answer the following question.

10/20/2015SCNM, PHYS 612, Introduction11 How does a cell in the adrenal cortex know to respond to adrenocorticotrophic hormone (ACTH)?

10/20/2015SCNM, PHYS 612, Introduction12 Receptors: Specificity: Affinity: K D = Half-Saturation Capacity:

10/20/2015SCNM, PHYS 612, Introduction13 Receptors: LIGAND AGONIST ANTAGONIST

10/20/2015SCNM, PHYS 612, Introduction14 Water Soluble Hormones: Membrane Protein: Second Messenger: Up/Down Regulation of Proteins Already Present: –Primarily by Phosphorylation/ Dephosphorylation Gene Regulation (Secondary)

10/20/2015SCNM, PHYS 612, Introduction15 Receptor Types: Serpentine Single Transmembrane –Ex. Insulin Receptor Cytokine (Growth Hormone/Prolactin) Guanylyl Cyclase-Linked

10/20/2015SCNM, PHYS 612, Introduction16 Second Messenger Systems:

Second Messengers Used by Serpentine Receptors 10/20/2015SCNM, PHYS 612, Introduction17

10/20/2015SCNM, PHYS 612, Introduction18 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

10/20/2015SCNM, PHYS 612, Introduction19 Phosphoinositol: Ligand Binds to Receptor G-protein linked to phospholipase C (PLC) PLC breaks polyphosphotidylinositol into diacylglycerol (DAG) and inositol triphosphate (IP 3 )

10/20/2015SCNM, PHYS 612, Introduction20 Phosphoinositol: IP 3 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

10/20/2015SCNM, PHYS 612, Introduction21 Phosphoinositol: Kinases (C-Kinase & CaM-Kinase –Phosphorylate Protein –Phosphorylate Transcription Activating Factors

Second Messengers Used by Receptors with a Single Transmembrane Domain 10/20/2015SCNM, PHYS 612, Introduction22

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

10/20/2015SCNM, PHYS 612, Introduction24 Cyclic-GMP: Membrane Bound Guanylyl Cyclase –Ligand Binds to Receptor –Receptor Coupled to Guanylyl Cyclase –Increase Intracellular cyclic-GMP –Activate G-Kinase –Phosphorylate Proteins

10/20/2015SCNM, PHYS 612, Introduction25 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

10/20/2015SCNM, PHYS 612, Introduction26 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

10/20/2015SCNM, PHYS 612, Introduction28 Membrane Receptor Degradation Receptor-Mediated Endocytosis –Clathrin Coated Pits –Endocytosis –Lysosomal Digestion of Ligand –Receptors Returned to Membrane Surface

LIPID SOLUBLE HORMONE RECEPTORS 10/20/2015SCNM, PHYS 612, Introduction29

10/20/2015SCNM, PHYS 612, Introduction30 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 10/20/2015SCNM, PHYS 612, Introduction31

Membrane Receptor 10/20/2015SCNM, PHYS 612, Introduction32

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 10/20/2015SCNM, PHYS 612, Introduction34

10/20/2015SCNM, PHYS 612, Introduction35 Negative Feedback Maintains level near a set point –Results in small oscillations about the set point –Ex: Thermostat/Heater –Ex: Blood Glucose

10/20/2015SCNM, PHYS 612, Introduction36 NEGATIVE FEEDBACK PANCREAS LIVER GLUCOSE TIME GLUCAGON BLOOD GLUCOSE

10/20/2015SCNM, PHYS 612, Introduction37 NEGATIVE FEEDBACK PANCREAS LIVER GLUCOSE TIME GLUCAGON BLOOD GLUCOSE

10/20/2015SCNM, PHYS 612, Introduction38 NEGATIVE FEEDBACK PANCREAS LIVER GLUCOSE TIME GLUCAGON BLOOD GLUCOSE

10/20/2015SCNM, PHYS 612, Introduction39 NEGATIVE FEEDBACK PANCREAS LIVER GLUCOSE TIME GLUCAGON BLOOD GLUCOSE

10/20/2015SCNM, PHYS 612, Introduction40 NEGATIVE FEEDBACK PANCREAS LIVER GLUCOSE TIME GLUCAGON BLOOD GLUCOSE

10/20/2015SCNM, PHYS 612, Introduction41 NEGATIVE FEEDBACK PANCREAS LIVER GLUCOSE TIME GLUCAGON BLOOD GLUCOSE

10/20/2015SCNM, PHYS 612, Introduction42 NEGATIVE FEEDBACK PANCREAS LIVER GLUCOSE TIME GLUCAGON BLOOD GLUCOSE

10/20/2015SCNM, PHYS 612, Introduction43 NEGATIVE FEEDBACK PANCREAS LIVER GLUCOSE TIME GLUCAGON BLOOD GLUCOSE

10/20/2015SCNM, PHYS 612, Introduction44 NEGATIVE FEEDBACK PANCREAS LIVER GLUCOSE TIME GLUCAGON BLOOD GLUCOSE

10/20/2015SCNM, PHYS 612, Introduction45 NEGATIVE FEEDBACK PANCREAS LIVER GLUCOSE TIME GLUCAGON BLOOD GLUCOSE

10/20/2015SCNM, PHYS 612, Introduction46 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!!!

10/20/2015SCNM, PHYS 612, Introduction47 POSITIVE FEEDBACK LH TIME PITUITARY GLAND OVARY LHE2E2

10/20/2015SCNM, PHYS 612, Introduction48 POSITIVE FEEDBACK LH TIME PITUITARY GLAND OVARY LHE2E2

10/20/2015SCNM, PHYS 612, Introduction49 POSITIVE FEEDBACK LH TIME PITUITARY GLAND OVARY LHE2E2

10/20/2015SCNM, PHYS 612, Introduction50 POSITIVE FEEDBACK LH TIME PITUITARY GLAND OVARY LH E2E2

10/20/2015SCNM, PHYS 612, Introduction51 POSITIVE FEEDBACK LH TIME PITUITARY GLAND OVARY LH E2E2

10/20/2015SCNM, PHYS 612, Introduction52 POSITIVE FEEDBACK LH TIME PITUITARY GLAND OVARY LH E2E2

10/20/2015SCNM, PHYS 612, Introduction53 Factors Affecting a Hormone’s Plasma Concentration Secretion Transport Metabolism Excretion

10/20/2015SCNM, PHYS 612, Introduction54 Secretion: Pulsatile Secretion Tonic vs Episodic Rhythms –Ultradian –Circadian –Monthly –Seasonal –Developmental

10/20/2015SCNM, PHYS 612, Introduction55 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

10/20/2015SCNM, PHYS 612, Introduction56 Metabolism Liver Other

10/20/2015SCNM, PHYS 612, Introduction57 Excretion Kidney Feces

10/20/2015SCNM, PHYS 612, Introduction58 Endocrinopathies Hypersecretion Hyposecretion Receptor Down-regulation/Inactivity Decreased Target Organ Conversion