Lecture # 12: Calcium homeostasis Hormones that regulate bone growth and calcium balance Parathyroid Hormone Vitamin D Calcitonin

Announcements Mini-exam #3 – Wed – sex diff, calcium Genes & Genomes Thurs 1:30-5:00 Brown & Goldstein

Food 1000 Feces 850 Small intestine 150 300 500 ECF 500 Cells Bone 8000 7850 Nephron Urine 150

variable variable Set point Effector Sensor, receptor Integrator, controller

Blood Ca+2 Blood Ca+2 Set point Effector Sensor, receptor Integrator, controller

Blood Ca+2 Blood Ca+2 Set point Effector Sensor, receptor Integrator, controller Parathyroid gland Parathyroid hormone PTH Parathormone

http://education. vetmed. vt http://education.vetmed.vt.edu/Curriculum/VM8054/Labs/Lab24/EXAMPLES/EXPARATH.HTM

Response to low Ca++ Blood Ca++ Blood Ca++ Intestine Ca++ absorption days Kidney Ca++ reabsorbed minutes Bone Bone resorption hours Calcium-sensing Receptor in PTH gland PTH Parathyroid gland

7-pass protein G-protein Coupled receptor GPCR 34 34

adenylyl cyclase G enzyme phospholipase C 2nd messenger effect 40 40

high Ca++ PTH cell ER Golgi vesicles IP3 DAG Ca++ 115 aa 90 aa 84 aa ER Golgi vesicles (-)

PTH on bone Increase blood Ca++ Bone breakdown Expect receptors on osteoclasts but receptors on osteoblasts

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.

Slow release of calcium Activates osteoclast proliferation, activity, break down mineralized bone

PTH Osteoblast IP3 cAMP Osteoclast RANKL RANK

PTH Osteoblast IP3 cAMP RANKL OPG Osteoprotegerin

PTH Osteoblast IP3 cAMP Estrogen + RANKL OPG RANK osteoclast activity

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

PTH on small intestine No direct effect Increase blood Ca++ Stimulate Ca++ absorption indirectly activate Vitamin D

Egg yolk, fish oil 1 alpha hydroxylase PTH 7-dehydrocholesterol UV SKIN UV cholecalciferol 1 alpha hydroxylase activates PTH D calcitriol http://uwcme.org/courses/bonephys/opvitD.html

melanocytes http://www.ultranet.com/~jkimball/BiologyPages/M/MSH.html

melanocyte

cytocrine

Vitamin D Receptor COOH NH2 Transcription activation domain DNA binding domain dimerization domain Vitamin D binding domain

Hormone Response Element Gene to be transcribed 17 17

= Transcription Factor Vit D RE mRNA protein Physiological effect 18 18

= Transcription Factor Vit D RE mRNA protein calbindin CaBP Physiological effect 18 18

Ca++ calmodulin Ca++ Na+ Ca++ calbindin Na+ Ca++-ATPase Ca++

Vitamin D effects Small intestine Kidney Bone Absorb Ca++ 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

Ca++ PTH cell IP3 DAG

Why do PTH cells have Vit D receptors? PTH gland PTH Ca++ (-) kidney Vit D Small intestine Ca++

Vitamin D effects Small intestine Kidney Bone Parathyroid gland Absorb Ca++ Kidney No effect (slight reabsorption) Bone Increase responsiveness to PTH Increase osteoclast production Parathyroid gland Decrease PTH synthesis

Rickets… could be prevented Eaton’s catalogue, 1919 http://uwcme.org/courses/bonephys/opmalacia.html http://timelinks.merlin.mb.ca/imagere4/ref1850.htm

C cells

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

Calcitonin function? Needed only occasionally? Not sure Prevent sudden increase blood Ca2+ when ingest a lot? Prevent Mom’s Ca2+ getting too high during pregnancy? Not sure

Food Feces Urine Small intestine ECF Cells Bone Nephron PTH D CT PTH D

- FALL Ca2+ intake Ca2+ absorbed Ca2+ in blood Osteoblast Osteoclast Calcitonin Osteoblast Osteoclast Estrogen Alendronate Ca2+ deposits Bone density Bone breaks FALL Surgery, pneumonia Death