1 Lecture # 12: Calcium homeostasis • Hormones that regulate bone growth and calcium balance – Parathyroid Hormone – Vitamin D – Calcitonin
Dec 30, 2015
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Lecture # 12: Calcium homeostasis
• Hormones that regulate bone growth and calcium balance– Parathyroid Hormone– Vitamin D– Calcitonin
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Announcements
• Mini-exam #3 – Wed – sex diff, calcium
• Genes & Genomes
• Thurs 1:30-5:00 Brown & Goldstein
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4
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BoneCells
Nephron
ECF
Small intestine
Food Feces
Urine
1000 850
150
300 150
8000 7850
500
500
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Integrator, controller
Sensor, receptorEffector
Set point variable variable
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Integrator, controller
Sensor, receptorEffector
Set pointBlood Ca+2Blood Ca+2
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Integrator, controller
Sensor, receptorEffector
Set pointBlood Ca+2Blood Ca+2
Parathyroid gland
Parathyroid hormone ParathormonePTH
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11 http://education.vetmed.vt.edu/Curriculum/VM8054/Labs/Lab24/EXAMPLES/EXPARATH.HTM
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Response to low Ca++
Blood Ca++
Parathyroid gland
Calcium-sensingReceptor
in PTH gland
PTH
Blood Ca++
Kidney
Ca++ reabsorbed
minutes
Bone
Bone resorption
hours
Intestine
Ca++ absorption
days
1334
GPCR
G-proteinCoupled receptor
7-pass protein
1440
G enzyme
2nd messenger
effect
phospholipase C
adenylyl cyclase
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PTH cell
IP3
DAG
115 aa
90 aa
84 aa
ERGolgi
vesicles
high Ca++
Ca++
(-)
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PTH on bone
• Increase blood Ca++
• Bone breakdown
• Expect receptors on osteoclastsbut receptors on osteoblasts
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Fast release of calcium
Activates calcium channels in osteocytes, so calcium transferred from bone fluid to osteocytes then via gap junctions to osteoblasts to blood.
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Slow release of calcium
Activates osteoclast proliferation, activity, break down mineralized bone
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OsteoblastPTH
RANKL
IP3cAMP
RANK
Osteoclast
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OsteoblastPTH
RANKL
IP3cAMP
OPG Osteoprotegerin
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OsteoblastPTH
RANKL
OPG
IP3cAMP
RANK
osteoclast activity
Estrogen
+
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PTH on kidney
• Increase blood Ca 2+
• Stimulate active transport of Ca 2+ from tubule
• Reabsorb 90% w/o PTH, 99% w/PTH
• Stimulate PO 4- excretion, so Ca 2+ doesn’t precipitate
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PTH on small intestine
• No direct effect
• Increase blood Ca++
• Stimulate Ca++ absorption indirectly– activate Vitamin D
24 http://uwcme.org/courses/bonephys/opvitD.html
Egg yolk, fish oil
1 alpha hydroxylase
PTH
activates
7-dehydrocholesterol
UV
SKIN
cholecalciferol
calcitriolD
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27http://www.ultranet.com/~jkimball/BiologyPages/M/MSH.html
melanocytes
28melanocyte
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cytocrine
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Vitamin D binding domain
DNA binding domain
dimerization domain
Transcription activation
domain
COOHNH2
Vitamin D Receptor
3217
HormoneResponseElement
Gene to be transcribed
3318
Vit D RE
mRNA
protein
Physiological effect
= Transcription Factor
3418
Vit D RE
mRNA
protein
Physiological effect
calbindin CaBP
= Transcription Factor
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Ca++
Na+
calbindin
Ca++
Ca++
Ca++
calmodulin
Ca++-ATPase
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Vitamin D effects
• Small intestine– Absorb Ca++
• Kidney– Slight reabsorption Ca++
• Bone– Indirect effect – more Ca++ deposited in bone
because increased Ca++ in blood– Via Vit D Receptor – move Ca++ out of bone
• Increase number of osteoclasts• Increase protein synthesis in osteoblasts• But these effects less obvious
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PTH cell
IP3
DAG
Ca++
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Why do PTH cells have Vit D receptors?
kidney
Small intestine
Vit D
PTH gland
PTH
Ca++
Ca++
(-)
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Vitamin D effects
• Small intestine– Absorb Ca++
• Kidney– No effect (slight reabsorption)
• Bone– Increase responsiveness to PTH– Increase osteoclast production
• Parathyroid gland– Decrease PTH synthesis
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Rickets… could be prevented
http://uwcme.org/courses/bonephys/opmalacia.html http://timelinks.merlin.mb.ca/imagere4/ref1850.htm
Eaton’s catalogue, 1919
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C cells
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32 aa
From C cells of thyroid gland
In response to high blood Ca2+
Lowers blood Ca2+ through effects on– kidney – increase excretion Ca2+ – bone – increase Ca2+ deposit
• CT receptors on osteoclasts –> detach from bone
– small intestine – slight decrease resorption
Calcitonin
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Needed only occasionally?Prevent sudden increase blood Ca2+ when
ingest a lot?
Prevent Mom’s Ca2+ getting too high during pregnancy?
Not sure
Calcitonin function?
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BoneCells
Nephron
ECF
Small intestine
Food Feces
Urine
D
PTH
PTH
PTH
D
CT
CT
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FALL
Ca2+ intake
Ca2+ absorbed
Ca2+ in blood
Osteoblast
Ca2+ deposits
Bone density
Bone breaks
Surgery, pneumonia
Death
OsteoclastAlendronate
Calcitonin
Estrogen-