KAAP630 regulation of calcium

Where are parathyroid glands?

On the back of the thyroid gland

What does High Ca++ levels in the blood stimulate?

Calcitonin release from thyroid (Decreases blood calcium)

What does Low Ca++ levels in blood stimulate?

PTH release from parathyroid (increases blood calcium)

Main functions of parathyroid hormone

1. Bone resorption and Ca++ into circulation

2. Ca+= Reabsorption in the kidney & phosphate excretion

3. Activation of vitamin D (Calcitriol)

Importance of blood calcium

Important for muscle contraction (skeletal, smooth, cardiac) neural, transmission, bone, etc

True or false

Very small amount of calcium in the blood; precisely controlled

True,

only 50% is ionized calcium, which can be used by the tissues, while 41% is protein-bound and can’t through capillary (determined by pH)

What can hypercalcemia cause?

depression of the nervous system

What can hypocalcemia cause?

Tetany in muscles

Skeleton and calcium

only 1% can be readily exchanged for blood calcium

Where can calcium be obtained?

Diet, less 50% absorbed by stomach, 99% filtered Ca++ from liver is reabsorbed and skeleton

What happens blood calcium levels fall

1. Blood calcium levels fall, stimulating the parathyroid glands to secrete parathyroid hormone

2. Parathyroid hormone increases calcium in 3 ways:

   • Release of stored calcium from bone (stimulation of osteoclasts more than osteoblasts

   • Enhanced reabsorption of calcium in kidneys

   • Stimulation of calcitriol(Active form of vitamin D) production at kidneys; enhanced Ca2+, PO43- absorption by digestive tract

     3. Blood calcium levels increase (return to homestasis)

What happens blood calcium levels rise

1. Rise in blood calcium levels stimulate thyroid gland to produce calcitonin

2. Calcitonin decreases calcium in 2 ways:

   • Increased excretion of calcium in kidneys

   • Calcium deposition in bone (inhibition of osteoclasts)

3. Blood calcium levels decline (return to homeostasis)

Pathway if there is high blood calcium levels (parathyroid - calcium sensing)

1. High levels of Ca++ bind to G protein coupled receptor

2. Activates phospholipase A2

3. Arachidonic acid

4. Leukotrienes

5. Leukotrienes inhibit PTH release and causes degradation

Pathway for Low blood calcium levels (parathyroid - calcium sensing)

1. Low levels of Ca++ detected

2. G protein coupled receptor relaxes to allow PTH release

3. Blood calcium levels rise

What is the biphasic response?

PTH that had be preformed can be released rapidly in response to acute changed in Ca++. Sustained low Ca++ then causes increased PTH synthesis

How does phosphate increase PTH? (calcium sensing)

By inhibiting phospholipase/AA formation (removes inhibitory effect)

Primary target of PTH

1. LOW blood Ca++ detected

2. Stimulates PTH release

3. Ca++ to be mobilized and released from bone or Ca++ to be reabsorbed in the kidney

4. Restore blood Ca++ levels

How does PTH stimulate bone for calcium?

1. PTH stimulates the RANKL and M-CSF ligands of osteoblasts

2. These RANKL and M-CSF ligands bind to the preosteoclasts receptors

3. This causes the preosteoclasts to mature into osteoclasts

4. Once matured, these osteoclasts secrete acids to break down bone to cause bone resorption

5. Calcium release into blood increases blood calcium levels

6. Bone resorption also releases phosphate which can use alkaline phosphate in blood as early marker of bone turnover

How does phosphate increase blood calcium?

It can use alkaline phosphate in blood as early marker of bone turnover

What does OPG do during PTH & bone?

OPG acts as a decoy and binds to RANK receptor and prevents RANKL ligand from binding to preosteoclast

-This results in no maturation of osteoclasts (bone breakdown) and more osteoblast function for bone building.

Estrogen and OPG

Estrogen increases OPG which inhibits osteoclast formation and allows for bone build up

How does PTH stimulate kidney for calcium reabsorption?

1. Ca++ reabsorption allows for an increase in Ca++ channels in the membrane, which allows Ca++ to be drawn back in

2. In distal tubule PTH inserts these Ca2+ channels into the luminal membrane

3. Calcium gets pulled back into the cell from the distal tubule and no longer excreted

4. PTH also converts Vitamin D into its active form which helps with the reabsorption of calcium

5. Vitamin D is activated through enzyme 1alpha-hydroylase

6. This active vitamin D stimulates carrier proteins called calbindin-D

7. The calbindin-D shuttles the luminal Ca+= entering from the distal tubule to the basolateral membrane

8. Active Vitamin D will also stimulate Ca2+ ATPase pump so the calcium is pumped into the interstitial space

How does PTH activate vitamin D?

1. Vitamin D is produced from the skin through UV light (sun)

Cholecalciferol (Vitamin D3) → Liver (25-hydroxycholecalciferol) → Kidney (PTH releases 1alpha-hydroxylase) → 1,25-Dihydroxycholecalciferol (Calcitriol) - Intestinal epithelium → activates calcium binding protein, calcium-stimulated ATPase, and Alkaline phosphatase → Intestinal absorption of calcium → Plasma calcium ion concentration

Where are vitamin D receptors located?

On nuclei stimulate transcription

PTH causes ____ in the proximal tubules of the _______ of ______ to ________

1. conversion

2. Kidneys

3. 25-hydroxycholecalciferol

4. 1,25-dihydroxycholecalciferol (active vitamin D or calcitriol)

What does Calcitriol do? (Active vitamin D)

Increases calcium absorption, decreases calcium excretion (promotes reabsorption), and promotes bone calcification and mineralization (Activates Ca2+ ATPase and calbindin-D carrier protein)

Hyperparathyroidism (Too much PTH)

-Usually from adenoma; overproduction of PTH. Can also be from kidney disease (low blood Ca++)

-S/S: High blood Ca++, bone loss/pain/fracture, increased urination, muscle weakness, kidney stones, twitches, heart palpitations

-Treatment: Surgery for adenoma, or medications

Hypoparathyroidism (Too little PTH)

-Results in low Ca++, high phosphorus (Less common)

What is “Hungry bones”

Following surgery for Adenoma, shift in bone metabolism from the chronic resorption to net bone formation, causing hypocalcemia