_ contains most of the Ca2+ stores in the body _ is the biologically active form of Ca2+ of the 60% . of unfilterable Ca2+, 10 % are _ and 50% are

Bones/Teeth Free, ionized 10% is complexed to anions 50% are free ionized

What are symptoms of hypocalcemia?

Hyperreflexia Spontaneous twitching Muscle cramps Numbness and tingling Tetany

What are two indicators of hypocalcemia?

Chvostek sign: twitching of the facial muscles elicited by tapping on facial nerve Trousseau sign: Carpopedal spasm upon inflation of blood pressure cuff

What are symptoms of hypercalcemia?

Decreased QT interval Constipation Lack of appetite Polyuria Polydipsia Muscle weakness Hyporeflexia Lethargy Coma

Hypocalcemia results in _ membrane excitability and is the basis for hypocalcemic tetany Hypercalcemia results in _ membrane excitability

Hypocalcemia-increased membrane excitability (reduces activation threshold for Na+ channels, easier to evoke AP) Decreased (Nervous system becomes depressed and reflexes are slowed)

What three organs are important in maintaining Ca2+ homeostasis? What three hormones are important in maintainin Ca2+ homeostasis?

Bone, kidney, intestine PTH, Vitamin D, Calcitonin

What is the relationship between Ca2+ and PO43- concentration in the ECF? Most Pi is distributed in _ The 1% that is in the plasma, some is _, some _ bound and some _

Inversely proportional to one another (high ca2+, low Pi) Both are regulated by the same hormones Most is distributed in bone (85%) Ionized (84%), Protein bound, Complexed to cations

PTH is secreted by _ cells in the _ gland _ is the stimuli for secretion Synthesis of PTH Synthesized as a _ Eleaved to form _ Transported to golgi and cleaved to form _ 84 aa's long with most biologically active portion of the hormone being located towards the _ terminus of the AA

Chief cells, Parathyroid Decreased serum Ca2+ preprohormone prohormone PTH N terminus (AAs 1-34)

Chronic hypercalcemia _ PTH synthesis and storage, and _ breakdown of stored _ and release of inactive fragments into the bloodstream Chronic hypocalcemia _ PTH synthesis and sotrage _ of parathyroid glands (2ndary _) Magnesium Parallels PTH secretion Severe Hypomagnesemia (EX: Alcoholism) _ of PTH storage, synthesis and secretion

Decrease, increase breakdown of stored PTH Increase PTH synthesis and storage Hyperplasia (2ndary hypoparathyroidism) Decrease

PTH acts on the bone and kidney tubule via which type of receptor?

GPCR (Gs) Increased cAMP and adenylyl cyclase and PKA

Regulation of Calcium and Phosphate Metabolism Flashcards by Madison Hahn

_ contains most of the Ca2+ stores in the body
_ is the biologically active form of Ca2+
of the 60% . of unfilterable Ca2+, 10 % are _ and 50% are

Bones/Teeth
Free, ionized
10% is complexed to anions
50% are free ionized

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What are symptoms of hypocalcemia?

Hyperreflexia
Spontaneous twitching
Muscle cramps
Numbness and tingling
Tetany

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What are two indicators of hypocalcemia?

Chvostek sign: twitching of the facial muscles elicited by tapping on facial nerve
Trousseau sign: Carpopedal spasm upon inflation of blood pressure cuff

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What are symptoms of hypercalcemia?

Decreased QT interval
Constipation
Lack of appetite
Polyuria
Polydipsia
Muscle weakness
Hyporeflexia
Lethargy
Coma

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Hypocalcemia results in _ membrane excitability and is the basis for hypocalcemic tetany
Hypercalcemia results in _ membrane excitability

Hypocalcemia-increased membrane excitability (reduces activation threshold for Na+ channels, easier to evoke AP)
Decreased (Nervous system becomes depressed and reflexes are slowed)

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Changes in calcium conentration can occur via what 3 primary ways?

Changes in plasma protein concentration
- Increase in plasma protein, increase in total Ca2+ concentration and vice versa
- No change in Ca2+ ionized (protein changes are usually more chronic issues)
Changing anion concentration
- Increase in Pi concentration will decrease Ca2+ ionized concentration
Acid-Base Abnormalities
- Alters ionized concentration by changing the fraction of Ca2+ bound to Albumin

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Changes in calcium levels during acidemia
Changes in calcium levels during alkalemia

Acidemia
- Increase in free ionized Ca2+ cuz less is bound to Albumin (H+ is taking Ca2+’s binding spots(
Alkalemia
- Decrease in free ionized Ca2+ because more is bound to Albumin (often is accompanied by hypocalcemia)

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What three organs are important in maintaining Ca2+ homeostasis?
What three hormones are important in maintainin Ca2+ homeostasis?

Bone, kidney, intestine
PTH, Vitamin D, Calcitonin

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Identify the following hormones in their role in Ca2+ homeostasis

Vitamin D
PTH
Vitamin D
Calcitonin
PTH (promotes reabsorption of Ca2+ and excretion of PO43-)

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What is the relationship between Ca2+ and PO43- concentration in the ECF?
Most Pi is distributed in _
The 1% that is in the plasma, some is _, some _ bound and some _

Inversely proportional to one another (high ca2+, low Pi)
Both are regulated by the same hormones
Most is distributed in bone (85%)
Ionized (84%), Protein bound, Complexed to cations

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PTH is secreted by _ cells in the _ gland
_ is the stimuli for secretion
Synthesis of PTH
- Synthesized as a _
- Eleaved to form _
- Transported to golgi and cleaved to form _
- 84 aa’s long with most biologically active portion of the hormone being located towards the _ terminus of the AA

Chief cells, Parathyroid
Decreased serum Ca2+
preprohormone
prohormone
PTH
N terminus (AAs 1-34)

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Regulation of PTH gene expression and secretion
- Increased Ca2+ levels in the blood are sensed by the _ receptor and activate _ and _ downstream signaling pathways to inhibit PTH gene transcription and exocytosis of PTH
- _ inhibits PTH gene transcription and promotes transcription of _ gene

CaSR
Gq and Gi (note Gq is inhibitory in this case)
1,25 Vitamin D-promotes CaSR gene transcription

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Chronic hypercalcemia
- _ PTH synthesis and storage, and _ breakdown of stored _ and release of inactive fragments into the bloodstream
Chronic hypocalcemia
- _ PTH synthesis and sotrage
- _ of parathyroid glands (2ndary _)
Magnesium
- Parallels PTH secretion
Severe Hypomagnesemia (EX: Alcoholism)
- _ of PTH storage, synthesis and secretion

Decrease, increase breakdown of stored PTH
Increase PTH synthesis and storage
Hyperplasia (2ndary hypoparathyroidism)
Decrease

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PTH acts on the bone and kidney tubule via which type of receptor?

GPCR (Gs)
Increased cAMP and adenylyl cyclase and PKA

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Action of PTH in the bone
Action of PTH on the kidney
Action of PTH on the intestine

Increase bone resorption
Increased reabsorption of Ca2+, Increased excretion of Pi and cAMP in the urine
Indirectly increases absorption of Ca2+ from intestine d/t actions of Vitamin D

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Function of Vitamin D

Properties of its synthesis

Has a _ receptor with what two receptor components

Functions
- Increase Ca2+ and Pi plasma concentrations
- Increase Ca2+ and Pi product to promote mineralization of new bone
- Has actions on intestine, kidney, and bone
Synthesis
- Made as a prohormone
- Hydroxylated at least twice to form an active metabolite
- Regulated by (-) feedback
- Has nuclear receptor (with Vitamin D receptor component and Retinoid X component)

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What enzyme converts 25 OH cholecalciferol to 1,25 dihydroxycholecalciferol and where is this enzyme located?
What stimulates this enzyme?

1 alpha hydroxylase, proximal tubule of the kidney
Low calcium and pi, high PTH

Renal 1 alpha hydroxylase is also known as _
Increased Ca2+ is sensed by the _ to inhibit transcription of the _ gene (acting via which GPCR receptor pathway?)
Increased PTH is sensed by GPCR and activates _, increasing the transcription of _ gene
1,25 dihydroxycholecalciferol inhibits transcription of _ gene and stimulates transcription of _ gene to produce 24 hydroxylase (AKA the inactive form of vitamin D)

CYP1alpha
CaSR, CYP1alpha (Gq,Gi)
Gs (cAMP/PKA), CYP1alpha
CYP1alpha, CYP24

PTH receptors are located on what cells in the bone?
Short term actions of PTH?
Long term actions of PTH on bone?
Vitamin D actions on bone?

PTH receptors are located on osteoblasts
Short term: PTH promotes bone formation (tx for osteoporosis)
Long term: Increase bone resorption (indirectly thru the release of cytokines from osteoblasts acting on osteoclasts)
Vitamin DL Stimulates osteoclast activity and bone resorption

Function of M-CSF

induces stem cells to differentiate into osteoclast precursors, mononuclear osteoclasts, and mature multinucleated osteoclasts

Function of RANKL

Receptor for NF-kB ligand
Cell surface protein produced by osteoblasts, bone lining cells, and apoptotic osteocytes
Primary mediator of osteoclast formation

RANK function

Cell surface protein receptor on osteoclasts and osteoclast precursors

OPG function

Produced by osteoblasts
Decoy receptor for RANKL:
Inhibits RANKL/RANK interaction

How does PTH work on the agents in bone formation/reabsorption?
How does vitamin D work on the agents in bone formation/reabsorption?

Increase RANKL, Decrease OPG
Increase RANKL

* How does PTH work on the kidney?

* PTH binds GPCR on basolateral surface of cell in proximal tubule of kidney * Activates Gs and cAMP/PKA * PKA phosphorylates Na+/Pi cotransporter on apical surface, preventing Pi reabsorption * cAMP is excreted w/ Pi

* How does Vitamin D promote Ca2+ absorption in the intestine?

* Increases transcription of : * Ca2+ transporter (**TRPV6) on apical membrane** * **Ca2+/3 Na+ exchanger on basolateral membrane** * **Calbindin**

* Summary of PTH actions on Ca2+ and Pi homeostasis

* Summary of Vitamin D actions on Ca2+ and Pi homeostasis

* Actions of calcitonin

* Responds to increase in blood Ca2+ * Decreases blood Ca2+ and Pi by inhibiting bone resorption (**Calcitonin receptors on osteoclasts)** * Decrease activity and number of osteoclasts * No role in chronic regulation of plasma Ca2+ * Thyroidectomy and thyroid tumors * Affect calcitonin levels but have no effect on Ca2+ metabolism

\_ is a steroid hormone that stimulates intestinal Ca2+ absorption and renal tubular Ca2+ absorption \_ promotes survival of osteoblasts and apoptosis of osteoclasts-favoring bone formation over resorption \_ is a steroid hormone that promotes bone resorption and renal Ca2+ wasting and inhbits Ca2+ absorption in the SI

* Estradiol 17 beta * Estrogen * Adrenal glucocorticoids

* ***Primary hyperparathyroidism*** * ***PTH levels*** * ***Ca2+ levels*** * ***Pi levels*** * ***Vitamin D levels***

* PTH levels increase * Ca2+ levels increase * Pi levels decrease * Vitamin D levels increase Sx: Stones, Bones, and Groans Hypercalciuria-stones Increased bone resorption-bones Constipation-groans Tx: Parathyroidectomy

* ***Secondary hyperparathyroidism*** * ***PTH levels*** * ***Ca2+ levels*** * ***Pi levels*** * ***Vitamin D levels***

* Increase in PTH levels secondary to low blood Ca2+ * Low blood Ca2+ causes: * Renal failure * Vitamin D deficiency * Levels * PTH increased * Low Ca2+ * Low Pi * Low Vitamin D

* ***Renal failure*** * ***PTH levels*** * ***Ca2+ levels*** * ***Pi levels*** * ***Vitamin D levels***

* PTH increased * Ca2+ decreased * Pi increased * Vitamin D decreased

* Hypoparathyroidism * Causes * Sx * Tx * Levels of: * PTH * Ca2+ * Pi * Vitamin D

* Causes * Thyroid/parathyroid surfery * AID or congenital * Sx (associated with hypocalcemia) * Muscle spasm or cramping * Numbness/tingling or burning around mouth and fingers * Seizures * In kides, poor tooth development and mental def * Tx: Oral Ca2+ supp and active form of Vitamin D * Levels * Decreased PTH * Decreased Ca2+ * Increased Pi * Decreased Vitamin D

* ***Albright hereditary osteodystrophy (Pseudohypoparathyroidism type 1a)***

* AD inherited * Gs for PTH in bone and kidney is defective * **Hypocalcemia nad hyperphosphatemia develop** * **Increase in PTH levels (administation of exogenous PTH doesn't do anything, no increase in urinary cAMP)** * **Short stature, short neck, obesity, subcutaneous calcification, shortened metatarsals and metacarpals** * **Levels:** * **PTH increased** * **Ca2+ decreased** * **Pi increased** * **Vit D decreased**

* ***Humoral hypercalcemia of malignancy***

1. PTHrP produced by tumor cells 2. Binds and activates the same receptor as PTH 3. **Decreased PTH levels** 4. **Decreased vitamin D** 5. **Increased urinary Ca2+** 6. **Increased urinary Pi and cAMP** 7. **Increased blood Ca2+** 8. **Decreased blood Pi**

* ***Familial hypocalciuric hypecalcemia (FHH):*** * ***PTH levels*** * ***Serum Ca2+ levels*** * ***Urine Ca2+ levels*** * ***Pi levels*** * ***Vitamin D levels***

* AD disorder d/t **mutations that inactivate CaSR in parathyroid glands and parallel Ca2+ receptors in ascending limb of the kidney** * **PTH** levels are normal or increased * **Serum Ca2+ elevated** * **Urine Ca2+ low** * **Pi normal** * **Vitamin D normal**

* ***Rickets***

* Impaired vitamin D metabolism d/t dietary def or resistance * Insufficient Ca2+ and Pi available to mineralize growing bonw * Characterized by growth failure and skeletal abnormalities * **2 Types:** * **Vitamin D Dependent Type I (Pseudovitamin D deficient)-diminished or lowered activity of alpha1hydroxylase** * **Vitamin D Dependent Type II (Pseudovitamin D deficient)-mutations in Vitamin D receptor** * Levels: * PTH: Increased (2ndary) * Ca2+: Normal or decreased * Pi: Decreased * Urine: Increased Pi and cAMP * Vitamin D: Decreased * Bone: Osteomalacia increases resorption

* ***Osteomalacia***

* New bones fail to mineralize * Bending and softening of weight bearing bones

* Tx for osteoporosis

* Anabolic Therapy * PTH * Antiresorptive therapy * Bisphosphates * Estrogen * Selective estrogen receptor modulators (SERMS: Raloxifene, Tamoxifen) * Calcitonin * RANKL inhibitors (Denosumab)