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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3
4
Food
1000
Small intestine
850
Feces
150
300
500
ECF
500
Cells
Bone
8000
7850
Nephron
5
Urine
150
variable
Effector
variable
Set point
Sensor, receptor
Integrator, controller
6
Blood Ca+2
Effector
Blood Ca+2
Set point
Sensor, receptor
Integrator, controller
7
Blood Ca+2
Blood Ca+2
Set point
Effector
Sensor, receptor
Integrator, controller
Parathyroid gland
Parathyroid hormone
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PTH
Parathormone
9
10
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http://education.vetmed.vt.edu/Curriculum/VM8054/Labs/Lab24/EXAMPLES/EXPARATH.HTM
Response to low Ca++
Blood Ca++
Blood Ca++
Ca++
Bone
reabsorbed resorption
Kidney
minutes
Bone
hours
Ca++
absorption
Intestine
days
Calcium-sensing
Receptor
in PTH gland
PTH
Parathyroid gland
12
7-pass protein
G-protein
Coupled receptor
GPCR
34
13
adenylyl
cyclase
G
enzyme
phospholipase C
2nd messenger
effect
40
14
high Ca++
PTH cell
IP3
DAG
Ca++
115 aa
(-)
15
ER
90 aa Golgi
84 aa vesicles
PTH on bone
• Increase blood Ca++
• Bone breakdown
• Expect receptors on osteoclasts
but receptors on osteoblasts
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Fast release of calcium
um channels in osteocytes, so calcium transferred from bone fluid to osteocytes then via gap junctions to osteobl
17
Slow release of calcium
Activates osteoclast proliferation, activity, break down mineralized bone
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PTH
IP3
Osteoblast
cAMP
RANKL
RANK
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Osteoclast
PTH
IP3
Osteoblast
cAMP
RANKL
OPG
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Osteoprotegerin
PTH
IP3
Osteoblast
cAMP
+
RANKL
Estrogen
OPG
RANK
osteoclast activity
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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
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7-dehydrocholesterol
Egg yolk, fish oil
SKIN
UV
cholecalciferol
1 alpha hydroxylase
activates
D
24
calcitriol
PTH
http://uwcme.org/courses/bonephys/opvitD.html
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melanocytes
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http://www.ultranet.com/~jkimball/BiologyPages/M/MSH.html
melanocyte
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cytocrine
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Vitamin D Receptor
COOH
NH2
Transcription
activation
domain
31
DNA
binding
domain
dimerization Vitamin D
domain
binding
domain
Hormone
Response
Element
Gene to be
transcribed
17
32
= Transcription Factor
Vit D RE
mRNA
protein
Physiological effect
18
33
= Transcription Factor
Vit D RE
mRNA
protein
calbindin
CaBP
Physiological effect
18
34
Ca++
calmodulin
Ca++
Ca++
calbindin
Na+
Ca++
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Ca++-ATPase
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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Ca++
IP3
DAG
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PTH cell
Why do PTH cells have Vit D receptors?
Ca++
PTH gland
PTH
kidney
Vit D
Small intestine
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
39
Rickets… could be prevented
Eaton’s catalogue, 1919
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http://uwcme.org/courses/bonephys/opmalacia.html
http://timelinks.merlin.mb.ca/imagere4/ref1850.htm
C cells
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Calcitonin
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
42
Calcitonin function?
Needed only occasionally?
Prevent sudden increase blood Ca2+ when
ingest a lot?
Prevent Mom’s Ca2+ getting too high
during pregnancy?
Not sure
43
Food
Feces
Small intestine
PTH
D
CT
ECF
PTH
Cells
CT
Nephron
44
Urine
PTH
D
Bone
Ca2+ intake
Ca2+ absorbed
Ca2+ in blood
Osteoblast
Calcitonin
Osteoclast
-
Estrogen
Alendronate
Ca2+ deposits
Bone density
FALL
Bone breaks
Surgery, pneumonia
45
Death