Calcium Regulation and Function in Biology

Calcium Regulation & the Parathyroid

• Calcium is a vital ion, both intracellularly and extracellularly
• A major component of bone (~50% bone weight), primarily as hydroxyapatite.
• 99% of calcium in bone and teeth.
• Cystolic calcium levels at rest are significantly lower than extracellular levels (~12,000-fold lower).
• Calcium levels are regulated through pumps, ion channels, and exchangers.
• Calcium plays a crucial role in neurons for synaptic transmission, initiating neurotransmitter release.
• Calcium is an intracellular messenger, impacting processes like muscle contraction.

Calcium as a Second Messenger

• Calcium is essential for cardiac muscle contraction—a discovery by Ringer in 1883
• Intracellular calcium triggers muscle contractions (Heilbrunn, 1940s)
• Calcium activates contractile proteins (e.g. troponin-C, actin) and regulates intracellular calcium levels via the sarcoplasmic reticulum (Ebashi, 1960s).
• Calmodulin is a ubiquitous calcium-sensing protein (discovered in 1973).

Calcium as a Signaling Molecule

• Calcium acts as a signaling molecule, influencing cellular activities like altering enzyme activity, exocytosis, and movement.

Cytosolic Calcium Changes in Signaling

• Significant increases in cytosolic calcium (up to 20-fold) occur in response to various stimuli.
• Fast signals trigger muscle contractions
• Sustained signals stimulate transmitter secretion
• Long-term changes affect gene expression

Intracellular Calcium Storage

• Intracellular calcium is primarily stored within the endoplasmic reticulum (ER) or the sarcoplasmic reticulum (SR) in muscle cells
• Calcium signaling is compartmentalised
• Calcium signaling exhibits variations in amplitude, frequency, and shape, including calcium sparks and puffs."

Calcium and Blood Clotting

• Calcium is necessary for blood clotting.
• Clotting factors X, VII, IX, and protein C contain calcium-binding domains

Calcium Signaling in Disease

• Calcium overload inside cells is toxic.
• This can cause muscle dysfunction (e.g., heart failure) and neurodegenerative processes (e.g., diabetic neuropathies, Alzheimer's disease).
• Disruption in ER calcium homeostasis contributes to beta-amyloid synthesis.
• High plasma calcium (hypercalcemia) can lead to cardiac arrhythmias and reduced neuromuscular transmission
• Low plasma calcium (hypocalcemia) causes tetany, epilepsy, and blood clotting problems

Extracellular Calcium Regulation

• Extracellular calcium (Ca2+) levels are carefully controlled by the body.
• Normal levels range from 2.2 to 2.55 mM

Calcium Fluxes in the Normal Adult

• Calcium is absorbed from the small intestine and is regulated based on various factors like PTH, calcitriol, and calcitonin
• Calcium moves actively through electrochemical gradients to maintain the delicate balance between bone, extracellular fluid (ECF), and kidneys

Bone Growth and Metabolism

• Bone growth and calcium metabolism are intertwined processes.
• Epiphyses are the ends of long bones.
• Diaphysis is the shaft of long bones and epiphyseal plates are crucial for bone growth.
• Bone growth occurs by dividing chondrocytes, which add length and are then replaced by bone tissue as it develops.

Bone Cells

• Osteoblasts are bone-forming cells that secrete osteoid (forming bone matrix) which is then mineralized
• Osteocytes mature from osteoblasts, no longer producing matrix but contributing to metabolism.
• Osteoclasts are responsible for resorbing and degrading existing bone, contributing to calcium regulation and bone remodeling, essentially the opposite of osteoblasts.

Osteoclasts

• Osteoclasts release hydrogen ions into the bone matrix to acidify the area.
• This acidification process weakens the mineral content of the bone matrix, causing the release of calcium ions.
• Hydrolytic enzymes (e.g., cathepsins) are released, dissolving the bone's organic components.

Osteoporosis

• Osteoporosis is a disease of bone growth and metabolism, where bone resorption exceeds deposition
• Potential factors are inadequate calcium intake, genetics, hormones, and smoking.
• Treatment often includes bisphosphonates which inhibit the activation of enzymes using pyrophosphate.

Soluble Factors Affecting Calcium Availability

• Hormones, as soluble factors, can influence the availability of calcium in the body.

Parathyroid Glands

• Four parathyroid glands are present, situated posteriorly to the thyroid gland, embedded within its lobes.
• Each is approximately 40-60mg in weight
• Variations exist in the number, size, and location of the parathyroid glands

Parathyroid Hormone (PTH)

• PTH is synthesized as a preprohormone by the parathyroid chief cells.
• The active form of PTH (84 amino acids) is cleaved from the preprohormone before its release.
• PTH release is triggered by low blood calcium levels; therefore is part of a negative feedback system, and high calcium inhibits release.
• PTH is released by exocytosis and is continuously synthesized though the body degrades it if not released.
• Vitamin D regulates PTH as a secondary mechanism.

PTH's Biological Activity

• PTH increases plasma calcium levels by decreasing plasma phosphate levels.
• PTH directly stimulates osteoclasts which release calcium and phosphate into the bloodstream, increasing bone resorption
• PTH causes an increase in calcium reabsorption and phosphate excretion in the kidney.
• PTH stimulates vitamin D3 synthesis, promoting calcium reabsorption in the intestine.

Calcium Regulation by PTH Secretion

• Calcium is the dominant regulator of PTH secretion.
• Continuous secretion of PTH.
• Maximum PTH secretion occurs at plasma Ca < 3.5 mg/dL.
• Parathyroid gland chief cells have specialized calcium receptors.
• Changes in extracellular fluid calcium trigger PTH release (seconds).

Hyperparathyroidism

• Hyperparathyroidism results from excessive PTH secretion due to benign tumors or hyperplasia of the parathyroid glands
• Hypercalcemia results from heightened bone resorption, intestinal calcium absorption, and renal tubular reabsorption
• This excessive PTH secretion leads to calcium homeostatic loss.
• The pathophysiology involves both PTH excess and concurrent increase in 1,25-(OH)2D, commonly from a solitary parathyroid adenoma
• Treatment usually entails hydration, intravenous bisphosphonates, or calcitonin for moderate cases; treating the underlying cause of the disorder in severe cases is advised.

Primary Hyperparathyroidism

• One of the most common endocrine disorders; often impacting women more than men (ratio 4:1).
• Typically sporadic, featuring a solitary parathyroid adenoma as a trigger.
• PTH increases blood Ca levels, causing bone damage via demineralization which causes bone cysts, and phalangeal erosion
• Surgical excision of the adenoma is often curative (>90% successful rate).

Hypoparathyroidism

• Hypoparathyroidism is a far less common condition than hyperparathyroidism.
• The causes include PTH deficiency (reduced or absent PTH synthesis). This could be due to inadvertent parathyroid tissue removal during surgery or synthesis of biologically inactive PTH.
• PTH resistance (pseudohypoparathyroidism) which results when there is a lack of proper response to given PTH or abnormalities in signalling.
• This often results from a congenital defect in PTH GPCR signalling.
• Treatment entails calcium and vitamin D supplementation.

Other Calcium-Regulating Hormones

• The primary calcium regulating hormones are PTH and Calcitonin.

Vitamin D

• Vitamin D is crucial for calcium homeostasis.
• It is obtained from sun exposure, diet, and supplements.
• Vitamin D synthesized in the skin is a precursor and requires hydroxylation reactions in the liver and kidneys (often stimulated by PTH) to be converted to calcitriol (1,25-dihydroxycholecalciferol), its biologically active form
• It is carried by vitamin D-binding protein (VDBP) to target cells
• It regulates genes for intestinal calcium uptake, bone mineralization, kidney phosphate uptake, thyroid & parathyroid function and immune function.
• Vitamin D deficiency is a frequent cause of hypocalcemia

Vitamin D Synthesis

• Vitamin D is synthesized from cholesterol via UV exposure or intake of foods rich in vitamin D or dietary supplements
• The precursor requires two sequential hydroxylation reactions to become active
• The first hydroxylation converts the vitamin into 25(OH)D, in the liver, followed by the second hydroxylation, in the kidneys to 1,25-(OH)2D.
• The second hydroxylation reaction is stimulated by parathyroid hormone.
• Active Vitamin D (calcitriol) promotes calcium absorption in the intestines and bone mineralization.

Vitamin D3

• Vitamin D3 is carried by vitamin D-binding protein (VDBP) and binds to nuclear receptors
• Regulates genes for important body functions like intestinal calcium uptake, bone mineralization, kidney phosphate uptake, and thyroid & parathyroid function, immune function and reduced inflammation

Calcitonin

• Calcitonin is secreted from C-cells in the thyroid gland
• Calcitonin acts to decrease plasma calcium levels, providing a physiological antagonist to PTH
• Calcitonin's role in normal calcium regulation is significant, but it may play a more crucial role in regulating bone remodeling
• Clinically, calcitonin is used to treat certain conditions like hypercalcemia and Paget's disease