T3/T4

E2/T

cortisol

nutrition

GHRHhypothalamus

GHpituitary

IGF-Iliver

Growth Platebone

(+)

Somatostatinhypothalamus

(-)

Let’s Cure Robert Wadlow

Hypothalamus

Pituitary

Liver

Bone

Group 1

Group 2

Group 3

Group 4

The Growth Axis

Endocrine Secretion:

Products, Pathways and Regulation

1. Overview and Quick Review

General Cell Biology

Regulation

2. One Example in More Depth

Glucose Regulation of Insulin Secretion

Neil Gesundheit, M.D., and Stephen J. Smith, Ph.D.neil7@stanford.edu, sjsmith@stanford.edu

Endocrine Signaling Depends on the Regulation of Hormone Secretion

Analyte or substrate regulation

HormoneRegulation

Hormones and Corresponding Secretory Pathways and Regulation Mechanisms Fall into Three Broad Patterns (almost…)

1.Peptides

2.Amines

3.Steroids

(The somewhat exceptional case of thyroid hormoneswill be treated at length in later lectures)

Synthesis and Secretion of the Peptide Hormones

Transcription TranslationGlycosylation

ProcessingPackaging

StorageExocytosis Circulation

Examples:Growth HormoneProlactinTSH, LH, FSH, hCGSomatostatinHypothal. Releas. Horm.InsulinGlucagonParathyroid HormoneMany, many others

DNA mRNA Prehormone Prohormone Hormone

Alpha and Beta Cells of Pancreatic Islets

How Do Vesicles Fuse?

SNARE complex of proteinsmerge the synaptic vesicle to the plasma membrane.

Free intracellular Ca++ activates the process.

[Ca++]

[Ca++]

Transcription TranslationGlycosylation

ProcessingPackaging

StorageExocytosis Circulation

Examples:Growth HormoneProlactinTSH, LH, FSH, hCGSomatostatinHypothal. Releas. Horm.InsulinGlucagonParathyroid HormoneMany, many others

DNA mRNA Prehormone Prohormone Hormone

RegulatedSecretion

Synthesis and Secretion of Peptide Hormones: the Anterior Pituitary Cell

GH Concentration(mcg/L)

(2 mcg/kg IV bolus)

10

20

30

GHRH Administration Produces Rapid Secretion of GH from the Anterior Pituitary

(Adapted from Maccario et al, J Clin Endo Metab 2001; 86:167-171)

GHRH

Synthesis and Secretion of Amine HormonesPrimary Regulation(acetylcholine frompreganglionic fibers via nicotinic receptors, leads to increases in free Ca++)

(PNMT)

Sympathetic neuronsSympathetic gangliaAdrenal medulla

Ultrastructure of Catecholamine Secretory Cells

Cat Adrenal Chromaffin Cells Sympathetic Nerve Ending onRat Chromaffin Cell

Steroid Secretion and Regulatory Pathways: the Adrenal Cortical Cell

• ACTH increases cholesterol uptake into mitochondrion• ACTH increases side-chain cleavage in mitochondrion, to produce pregnenolone

Steroid Secretion and Regulatory Pathways: Side-Chain Cleavage in the Mitochondrion of the Adrenal Cortical Cell

• ACTH increases cholesterol uptake into mitochondrion• ACTH increases side-chain cleavage in mitochondrion, to produce pregnenolone

PregnenoloneCholesterol

Side-chain cleavage enzyme

Cortisol concentrations after SQ injection of synthetic ACTH

Cosyntropin (synthetic ACTH) administration at time 0

0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0

Time (hours)

ACTH

Let me challenge you…

How would you predict that the beta cell would regulate the secretion of insulin?

How does the beta cell sense high and low glucose concentrations?

The Regulation of Insulin Secretion fromPancreatic Beta Cells by Glucose

1. In spite of long and intensive searching, no beta-cell “glucose receptor” has been identified

2. Glucose metabolism itself is the glucose “sensor” (Frances Ashcroft)

3. Electrophysiological and ionic mechanisms couple intracellular ATP to insulin secretion

K Channel Closure is Linked to Insulin Secretion via Closing of ATP-Sensitive K Channels and Consequent Opening of Voltage-Dependent Ca Channels

Sulfonylurea Oral Anti-Diabetic Drugs Act By Promoting the Closing of ATP-Sensitive Potassium Channels

Take Home Points

Secretion of peptides and amines occurs via secretory vesicles (they are “pre-packaged”), is regulated, and Ca++ from intracellular sources is the key signaling molecule for secretion

Secretion of steroid and thyroid hormones occurs by increasing substrate; these hormones are not packaged/stored in secretory vesicles

Secretion of insulin is unique: sensing is by changing concentrations of a by-product of glycolyis, ATP; Ca++ triggers secretion and is from extracellular sources

Goal of this module is to have you engage in joyful learning!