Hormonal Control of Calcium Homeostasis

Intracellular calcium

- Majority of calcium in mitochondria and ER - Concentrations fluctuate greatly (100 nM to 1 uM) Integral to calcium's role in intracellular signaling, enzyme activation and muscle contractions

Primary hyperparathyroidism

- parathyroid gland disease - most commonly due to a parathyroid tumor (adenoma) which secretes PTH without proper regulation. - symptoms: chronic elevations of blood calcium concentration (hypercalcemia), kidney stones and decalcification of bone

Milk Fever - Predisposing Factors

1. Cold stress: subzero temperatures can induce hypocalcaemia 2. Body condition: milk fever is more prevalent in over-fat cows (fatty liver) than in thin cows à mobilization of fatty acids can affect blood calcium levels 3. Breed: some breeds of cows are more susceptible 4. Age: older cows have increased milk production and greater demands for calcium

Importance of Calcium

1. Structural component (with phosphate) of bones, teeth 2. Blood clotting 3. Maintain transmembrane potential of cells (along with Na+ and K+) 4. Muscle contraction 5. Second messenger in hormonal and neurocrine signal transduction

Histology of the Parathyroid Gland

1.) Chief cells: source of PTH; most numerous 2. oxyphil cells: unknown function, appear at puberty, increase in number with age.

Distribution of Calcium

1.) Intracellular Calcium 2.) Blood and Extracellular Fluid 3.) Bone

Hormones that Regulate Calcium Homeostasis

1.) Parathyroid 2.) Vitamin D 3.) Calcitonin

Calcitonin (CT)

A hypocalcemic hormone (↓ blood Ca2+) A 32 amino acid polypeptide hormone synthesized by parafollicular "C cells" of the thyroid gland Release is stimulated by elevated blood Ca2+ level

Parathyroid Hormone Secretion

Calcium concentrations fall below the normal range, there is a steep increase in secretion of parathyroid hormone Low levels of the hormone are secreted even when blood calcium levels are high

Blood and extracellular fluid

Concentration approximately 1 mM, or 10,000X the basal concentration of free calcium within cells.

Pathophysiology

Critical to maintain blood calcium concentrations within a tight normal range. Deviations above or below the normal range frequently lead to serious disease. Hyper and hypcalcemia.

Ca 2+ Physiology

Cytosolic and extracellular fluid physiology must be maintained within narrow limits despite wide fluctuations in Ca2+ intake. It is a key element in numerous physiological functions Derived from diet or as a structural component of bone

hormones regulate calcium homeostasis

PTH increases blood calcium and vitamin d synthesis. Vitamin D increases calcium absorption in the intestine. Calcitonin inhibits bone resorption.

Parathyroid Hormone (PTH)

PTH is a single-chain polypeptide hormone of 84 amino acids. PTH is a hypercalcemic hormone (↑ blood Ca2+) Control of PTH secretion = circulating Ca2+ levels Parathyroid cells (chief cells) have recognition sites for Ca2+ - calcium sensing receptors (CaSR) - seven-spanning membrane G-protein coupled receptor

Calcium Regulation

Regulation of calcium homeostasis occurs via transfer of calcium between the blood and 3 major target organs: bone, intestine, kidney.

Mechanism of PTH Release

Review Notes

Milk Fever: Prevention

The DCAD method • Feeding a calcium-deficient diet • Higher dietary magnesium If total absorbed diet calcium is substantially less than required by the cow, it is possible to stimulate the secretion of PTH before calving which can stimulate bone Ca resorption and intestinal Ca absorption mechanisms prior to calving to prevent milk fever

Function of Calcitonin

The main function of calcitonin is to inhibit bone resorption by inhibiting osteoclasts (breakdown of bone) 1. stimulates osteoblasts to form bone taking calcium out of the circulation 2. inhibits the mobilization of bone (and calcium) by osteoclasts 3. end result is a decrease in the level of calcium in the blood thus helping to maintain proper blood calcium levels

Bone

The majority of body calcium is in bone 99% of the calcium is tied up in the mineral phase The remaining 1% is in a pool that can rapidly exchange with extracellular calcium

Reabsorption

The process of re-absorbing (absorbing again)

Resorption

The processes of breaking down and assimilating (CA 2+ mobilization)

Calcium Regulation - Small Intestine

The site where dietary Ca2+ is actively transported across mucosa. Dependent on expression of a Ca2+ -binding protein in epithelial cells.

Calcium Regulation - Bone

The vast reservoir of Ca2+ (immediate source of Ca2+) Stimulates resorption of bone mineral releases Ca2+ and phosphate into blood

Calcium Regulation - Kidney

Under normal blood Ca2+ concentrations, almost all of the Ca2+ that enters glomerular filtrate is reabsorbed from the tubular system back into blood, which preserves blood Ca2+ concentration. If tubular reabsorption of Ca2+ decreases, Ca2+ is lost by excretion into urine.

Secondary hyperparathyroidism

disease outside of the parathyroid gland leads to excessive secretion of PTH - kidney disease - kidneys are unable to reabsorb Ca2+, blood calcium levels will fall, stimulating continual secretion of PTH to maintain Ca2+ levels in blood - inadequate nutrition - for example, diets that are deficient in Ca2+ or vitamin D - ↑decalcification of bone, leading to pathologic fractures or "rubber bones".

Milk Fever

economically important metabolic condition that occurs at the onset of lactation - can reduce the productive life of a dairy cow • clinical symptoms include: - reduced appetite and rumen motility - inhibition of urination and defecation - lateral recumbency - eventual coma and death • cows recovering from milk fever have greater incidence of: - ketosis, mastitis, dystocia, retained placenta, displaced placenta and uterine prolapse

Hypoparathyroidism

typically results in decreased Ca2+ blood (HYPOCALCEMIA) • causes include surgical removal of the parathyroid glands and disease processes that lead to destruction of parathyroid glands • leads to tetany and convulsions, and can be acutely lifethreatening • treatment focuses on restoring normal blood calcium concentrations by calcium infusions, oral calcium supplements and vitamin D therapy

Parathyroid Glands

• Generally two pairs, located behind the thyroid gland • About 2-5% of the human population has supernumerary parathyroids (usually 6 to 8 glands) • The parathyroid glands evolved from gills, which also regulate calcium and ionic balance in fishes • Parathyroid glands are not associated with thyroid in birds, reptiles, amphibians

Milk Fever: Treatment

• supplementing blood calcium levels until the bone and intestinal transport systems adapt to provide the necessary calcium • should be implemented as early as possible • most common à IV injection of calcium salts, usually calcium borogluconate • must be administered slowly as it can result in cardiac arrest • calcium and phosphorus supplements (oral gels) can also be given around parturition

Vitamin D

•Also known as cholecalciferol • acts to ↑ blood [Ca2+] • not actually a vitamin, instead a precursor of a steroid-like hormone • generated through the activity of PTH within the kidney • the most important effect of VitD is to facilitate absorption of Ca2+ from the small intestine • in concert with PTH, VitD also enhances fluxes of Ca2+ out of bone