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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, [email protected], [email protected]
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!