1. Let’s Cure Robert Wadlow
The Growth Axis
Hypothalamus
Somatostatin
hypothalamus
GHRH
hypothalamus
Group 1
(-)
(+)
Pituitary GH
pituitary
Group 2
Liver
IGF-I
liver
Group 3
This slide illustrates the GH axis in humans. Each group has to devise a way to cure Robert.
T3/T4
cortisol
Bone
Growth Plate
bone
Group 4
E2/T
nutrition

2. Endocrine Secretion: Products, Pathways and Regulation
Overview and Quick Review
General Cell Biology
Regulation
One Example in More Depth
Glucose Regulation of Insulin Secretion
Neil Gesundheit, M.D., and Stephen J. Smith, Ph.D.

3. Endocrine Signaling Depends on the Regulation of Hormone Secretion
Analyte or substrate regulation

4. Peptides Amines Steroids
Hormones and Corresponding Secretory Pathways and Regulation Mechanisms Fall into Three Broad Patterns (almost…)
Peptides
Amines
Steroids
(The somewhat exceptional case of thyroid hormones
will be treated at length in later lectures)

5. Synthesis and Secretion of the Peptide Hormones
Examples:
Growth Hormone
Prolactin
TSH, LH, FSH, hCG
Somatostatin
Hypothal. Releas. Horm.
Insulin
Glucagon
Parathyroid Hormone
Many, many others
Transcription
Translation
Glycosylation
Processing
Packaging
Storage
Exocytosis
Circulation
DNA mRNA
Prehormone
Prohormone
Hormone

6. Alpha and Beta Cells of Pancreatic Islets

7. How Do Vesicles Fuse? [Ca++] [Ca++] SNARE complex of proteins
merge the synaptic vesicle to
the plasma membrane.
Free intracellular Ca++ activates
the process.
“SNARE” is an acronym derived from "SNAP (Soluble NSF Attachment Protein) REceptors” Thomas Sudhof is Stanford scientist and Nobel laureate who worked out many of these mechanisms
[Ca++]
[Ca++]

8. Synthesis and Secretion of Peptide Hormones: the Anterior Pituitary Cell
Examples:
Growth Hormone
Prolactin
TSH, LH, FSH, hCG
Somatostatin
Hypothal. Releas. Horm.
Insulin
Glucagon
Parathyroid Hormone
Many, many others
Regulated
Secretion
Transcription
Translation
Glycosylation
Processing
Packaging
Storage
Exocytosis
Circulation
DNA mRNA
Prehormone
Prohormone
Hormone

9. GHRH Administration Produces Rapid Secretion
of GH from the Anterior Pituitary 30
GHRH
(2 mcg/kg IV bolus)
GH Concentration
(mcg/L) 20 10
(Adapted from Maccario et al, J Clin Endo Metab 2001; 86: )

10. Synthesis and Secretion of Amine Hormones
Primary Regulation
(acetylcholine from
preganglionic fibers via nicotinic
receptors, leads to increases in free
Ca++)
Sympathetic neurons and sympathetic ganglia
(PNMT)
Sympathetic neurons
Sympathetic ganglia
Adrenal medulla

11. Ultrastructure of Catecholamine Secretory Cells
Cat Adrenal Chromaffin Cells
Sympathetic Nerve Ending on
Rat Chromaffin Cell

12. Steroid Secretion and Regulatory Pathways: the Adrenal Cortical Cell
Cholesterol has 27 carbons. Pregnenolone has 21 carbons. The side-chain cleavage enzyme works through 3 enzymatic steps – 2 hydroxylations and one hydrolysis/cleavage – to remove 6 carbons. Side-chain cleavage is the rate-limiting step in the biosynthesis of the steroid hormones.
ACTH increases cholesterol uptake into mitochondrion
ACTH increases side-chain cleavage in mitochondrion,
to produce pregnenolone

13. Steroid Secretion and Regulatory Pathways: Side-Chain Cleavage in the Mitochondrion of the Adrenal Cortical Cell
Cholesterol
Pregnenolone
Side-chain
cleavage enzyme
Cholesterol has 27 carbons. Pregnenolone has 21 carbons. The side-chain cleavage enzyme works through 3 enzymatic steps – 2 hydroxylations and one hydrolysis/cleavage – to remove 6 carbons. Side-chain cleavage is the rate-limiting step in the biosynthesis of the steroid hormones.
ACTH increases cholesterol uptake into mitochondrion
ACTH increases side-chain cleavage in mitochondrion,
to produce pregnenolone

14. 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)

15. 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?

16. The Regulation of Insulin Secretion from Pancreatic Beta Cells by Glucose
In spite of long and intensive searching, no beta-cell “glucose receptor” has been identified
Glucose metabolism itself is the glucose “sensor” (Frances Ashcroft)
Electrophysiological and ionic mechanisms couple intracellular ATP to insulin secretion

17. K Channel Closure is Linked to Insulin Secretion via Closing of ATP-Sensitive K Channels and Consequent Opening of Voltage-Dependent Ca Channels
The biology of ATP-mediating glucose sensing and how it regulates insulin secretion is largely the work of Frances Ashcroft, PhD., a famous Oxford scientist.

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

19. 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!