Calcium Homeostasis

General Features of Calcium Homeostasis

Localization and Function of Calcium

(1) Bone/Cartilage (1 kg, 99% total body Ca⁺⁺)-bone integrity(1.5-2% bone mass), buffer for plasma Ca⁺⁺-variable conc.

bone phosphate – about 0.6 kg, concentration also variable

(2) Intracellular (4 g, 0.9% of total body Ca⁺⁺) – second messenger; oscillating concentration (50 nM to 1-10 m M)

intracellular phosphate – about 100 g, concentration relatively fixed (0.5 mM)

(3) Extracellular (serum) (1 g, 0.1% of total) – coagulation, muscle and nerve excitability; fixed concentration (at 1.3 mM)

extracellular phosphate – about 0.5 g, concentration 0.8-1.5 mM

Daily Events

each day kidney filters 1% of total body Ca⁺⁺ (10g Ca⁺⁺, 6g PO₄^2-) and excretes 5% of what is filtered (0.4g Ca⁺⁺, 1g PO₄^2-)
0.6 g Ca⁺⁺ and 0.2 g PO₄^2- are used in bone turnover every day

Intracellular Calcium Homeostasis – sole function is to transmit information

free [Ca⁺⁺] oscillates and is regulated, total Ca⁺⁺ is much higher

if free intracellular [Ca⁺⁺] increases (nM to m M), Ca⁺⁺ will bind to specific Ca⁺⁺-binding pockets of several cell proteins

what causes Ca⁺⁺ levels to change?

Ca⁺⁺ channels – voltage-sensitive, receptor-dependent, SR or ER

Ca⁺⁺ pumps – ATPases of SR/ER, plasma membranes

Na⁺/Ca⁺⁺ exchanger – secondary active transport

calmodulin – classical example of a Ca⁺⁺ binding protein, with four Ca⁺⁺binding sites

Ca⁺⁺ in Myocyte Contraction – sequence of events:

resting Ca⁺⁺ concentration/voltage gradient maintained by lipid membrane

depolarization (via Na⁺ entry) causes transient opening of Ca⁺⁺ plasma membrane channels

resulting Ý in [Ca⁺⁺] triggers opening of SR and ER Ca⁺⁺channels – this accounts for 95% of [Ca⁺⁺] used for contraction

ÝÝ [Ca⁺⁺] causes SR and plasma membrane Ca⁺⁺ATPases to pump Ca⁺⁺ out of the cytosol

drugs that affect this process:

(1) Ca⁺⁺ channel blockers-block plasma membrane Ca⁺⁺ channel-ß response to depolarization and myocyte activity

(2) Digitalis-Ý intracellular [Na⁺] (competitive inhibition of Na⁺/K⁺ ATPase), so Na⁺/Ca⁺⁺ antiporter cannot ß [Ca⁺⁺]

higher intracellular [Ca⁺⁺] means that the cell cannot respond to Ca⁺⁺ changes as well

(3) Catecholamines-Ý cAMPÞ phosphorylation of SR and plasma membrane Ca⁺⁺ ATPases (faster removal of Ca⁺⁺)

Extracellular Calcium Homeostasis

Plasma Ca⁺⁺ – total amount is usually about 2.5 mM (10 mg/dL), but free Ca⁺⁺ is kept constant at 1.2 mM

usually, about 48% is free; 46% is protein bound, 6% bound to phosphate, citrate, etc.

total plasma Ca⁺⁺ is increased by PTH and vitamin D; decreased by calcitonin

free ionized Ca⁺⁺ must be kept at very precise levels, since it regulates the physiological response of tissues

Dietary Intake-essential since 0.6g Ca⁺⁺ and 0.3g PO₄^2- are lost each day even when Ca⁺⁺ and PO₄^2- are maximally conserved

recommended daily intake is 1.3 g Ca⁺⁺, 1 g PO₄^2-, 0.6 g Mg⁺⁺

daily requirements:

1-3 yrs of age – 0.5 g
3-12 yrs – 0.8 g
12-19 yrs – 1.3 g
19-50 yrs – 1.0 g
>50 yrs – 1.3 g
pregnancy – 1.3 g

Ca⁺⁺-rich foods – Ca⁺⁺ is relatively abundant in fish, but there are exceptions (lobster, storks in siberia, incas); other foods:

cheese (1.5 oz) – 0.3 g
tofu (1 cup) – 0.3 g
spinach (1 cup) – 0.2 g
milk (1 cup) – 0.3 g
broccoli (1 cup) – 0.2 g

Derangements in Ca⁺⁺ Homeostasis – what organ systems can affect total extracellular Ca⁺⁺ levels?

intestine – malabsorption of Ca⁺⁺ and PO₄^2-, lack of Ca⁺⁺ in diet, presence of Ca⁺⁺-complexing agents (oxylate in spinach)

kidney – filtration and vitamin D activation

skin – decreased light exposure Þ decreased vitamin D synthesis

parathyroid gland and bone

Hypocalcemia – [Ca⁺⁺] < 1.1 mM

muscle stiffness, contracture, hyperexcitability of nerves, anxiety, ß in cardiac contractility, seizures, cardiac arrest

Hypercalcemia – [Ca⁺⁺] > 1.5 mM

polyuria, constipation, fatigue, calcium deposit, cardiac arrhythmia

Vitamin D

Synthesis – made from 7-dehydrocholesterol in skin through UV irradiation – produces cholecalciferol (Vitamin D₃)

Metabolism – vit D is transported to the liver where it is hydroxylated to 25-OH Vitamin D – very little biological activity

25-OH vit D is transported to kidney bound to plasma protein and hydroxylated to 1,25-(OH)₂ vit D in kidney mitochondria

The only really active form of vitamin D is 1,25-(OH)₂ Vit D – made in the kidney

the enzyme responsible for synthesis of this molecule requires e^- transport, NADPH and ferredoxins

synthesis is activated by low PO₄^2- or high PTH; high Ca⁺⁺ and PO₄^2- levels cause 25-OH Vit D Þ 24,25-(OH)₂ vit D

since precursors are inactive, vit D overdose is rare

overdose has been reported in infants and cows due to high levels of 1,25-(OH)₂ vit D in grass

Mechanism of Action – net effect is to Ý plasma [Ca⁺⁺] and [PO₄^2-]

main site of action is intestine where it acts to increase absorption of Ca⁺⁺ and PO₄^2-

precise mechanism unknown – perhaps Ý intestinal microvilli Ca⁺⁺ binding proteins

Parathyroid Hormone (PTH)

Anatomy – four small glands behind the thyroid (position and number of glands may vary)

Histology – chief cells are the predominant cell and produce PTH; oxyphil cells also present.

Action – PTH is a peptide hormone secreted by the parathyroid gland in response to low plasma [Ca⁺⁺]

unlike vitamin D, PTH increases plasma [Ca⁺⁺] in the absence of dietary Ca⁺⁺

Synthesis – PTH is an 84 amino acid peptide secreted by exocytosis of the parathyroid granules

all biologic activity is found in amino acids 1-34; 1-2 are necessary for cellular response, 3-34 for binding to the receptor

Measurement – two methods

(1) Bioassays – based on cAMP production in osteosarcoma cell lines – sensitive but expensive

(2) Radioimmunoassays – inexpensive but less accurate; more common clinically

antisera are directed against entire protein, since N-terminal (active) fragments are often low in serum
fragments of PTH are cleared by glomerular filtration; renal failure can cause an abnormally high PTH

Regulation of PTH Secretion – regulation occurs by free plasma Ca⁺⁺ levels.

Serum [Ca⁺⁺] > 1.6 mM Þ no PTH secretion occurs.

Serum [Ca⁺⁺] < 1.1 mM Þ maximal PTH secretion

Mechanism of Action – PTH primarily Ý plasma [Ca⁺⁺] by activating osteoclasts (Ý bone resorption)

also causes Ý kidney PO₄^2- clearance and Ý Ca⁺⁺ reabsorption

if PTH is present, 99.5% of Ca⁺⁺ is reabsorbed by nephron

70% reabsorbed in the proximal tubule (80% paracellular, 20% transcellular)
30% in the distal tubule (entirely transcellular)

Calcitonin (CT)

Structure – linear 32 amino acid polypeptide – all amino acids are necessary for biological response.

Synthesis – produced by parafollicular cells of thyroid (C-cells)

fish contain many isoforms of calcitonin and up- or downregulate expression depending on water [Ca⁺⁺]

Mechanism of Actions – ß resorption of bone Ca⁺⁺ and PO₄^2-, Ý renal clearance of Ca⁺⁺ and PO₄^2-

importance of calcitonin in humans under normal conditions is not known
calcitonin is often found to be elevated or decreased under different circumstances

Diseases Related to Calcium Homeostasis

(1) Hyperthyroidism – Rare, Primary adenoma usually MEN (multiple endocrine neoplasia).

Symptoms – similar to hypercalcemia and hypophosphatemia

Coma and weakness
Bone reabsorption
Bone deposit in soft tissues
Nephrocalcinosis

Lab Findings – high serum PTH, hypercalcemia, decreased PO₄^2- clearance

(2) Hypoparathyroidism – Usually secondary to thyroid surgery and damage to the parathyroid gland

Symptoms – muscle irritability, osteosclerosis

Lab Findings – hypocalcemia, hyperphosphatemia

(3) Osteoporosis – loss of bone mass per unit volume; existing bone is normal

most common forms are senile osteoporosis and premenopausal osteoporosis

more common in women due to lesser peak bone mass

Possible Causes – insufficient dietary intake of Ca⁺⁺, PO₄^2-, Mg⁺⁺, Vit D

lack of exercise or immobilization Þ Ý Bone resorption Þ Ý serum [Ca⁺⁺] Þ ß PTH Þ ß Ca⁺⁺ uptake

hormonal imbalance – testosterone, estrogen, thyroid hormone

(4) Diet-induced hyperparathyroidism

Ca⁺⁺ and PO₄^2- are regulated together, since most natural foods contain equal amounts of each
soft drings and fast foods contain considerably more PO₄^2- than Ca⁺⁺

PTH is only able to handle slight discrepancies in Ca⁺⁺ and PO₄^2- – modern diets can lead to excessive PTH secretion