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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-