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Let’s Cure Robert Wadlow
The Growth Axis
Hypothalamus
Somatostatin
GHRH
hypothalamus
hypothalamus
(-)
(+)
GH
Pituitary
Group 2
pituitary
IGF-I
Liver
Group 3
liver
T3/T4
cortisol
Growth Plate
Bone
Group 4
bone
E2/T
Group 1
nutrition
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.
[email protected], [email protected]
Endocrine Signaling Depends on the
Regulation of Hormone Secretion
Hormone
Regulation
Analyte or substrate regulation
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 hormones
will be treated at length in later lectures)
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
DNA mRNA
Translation
Glycosylation
Prehormone
Processing
Packaging
Prohormone
Storage
Exocytosis
Hormone
Circulation
Alpha and Beta Cells of Pancreatic Islets
How Do Vesicles Fuse?
SNARE complex of proteins
merge the synaptic vesicle to
the plasma membrane.
Free intracellular Ca++ activates
the process.
[Ca++]
[Ca++]
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
DNA mRNA
Translation
Glycosylation
Prehormone
Processing
Packaging
Prohormone
Storage
Exocytosis
Hormone
Circulation
GHRH Administration Produces Rapid Secretion
of GH from the Anterior Pituitary
30
GH Concentration
(mcg/L)
GHRH
(2 mcg/kg IV bolus)
20
10
(Adapted from Maccario et al, J Clin Endo Metab 2001; 86:167-171)
Synthesis and Secretion of Amine Hormones
Primary Regulation
(acetylcholine from
preganglionic fibers via nicotinic
receptors, leads to increases in free
Ca++)
(PNMT)
Sympathetic neurons
Sympathetic ganglia
Adrenal medulla
Ultrastructure of Catecholamine Secretory Cells
Cat Adrenal Chromaffin Cells
Sympathetic Nerve Ending on
Rat 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
Pregnenolone
Cholesterol
Side-chain
cleavage enzyme
• ACTH increases cholesterol uptake into mitochondrion
• ACTH increases side-chain cleavage in mitochondrion,
to produce pregnenolone
Cortisol concentrations after SQ injection of synthetic ACTH
ACTH
Cosyntropin (synthetic ACTH)
administration at time 0
0.5
1.0
1.5
2.0
2.5
3.0
Time (hours)
3.5
4.0
4.5
5.0
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 from
Pancreatic 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!
