I've already mentioned some of the functions of calcium here, but here are some more!
- Clotting- many clotting factors are activated by calcium
- Endocrine system- calcium is required for exocytosis of hormones (and other things)
Calcium levels are also important for regulating neuromuscular activity. When calcium levels are too high (hypercalcaemia), calcium binds to the activation gate of Na+ channels, making the membrane less permeable to sodium (and the cell less excitable). On the other hand, when calcium levels are too low, nerves and muscles become hyperexcitable. These phenomena are responsible for many of the symptoms of hyper- and hypocalcaemia.
99% of calcium is stored in the bone as hydroxyapatite. Around 1% is stored in cells (mainly in the mitochondria and endoplasmic reticulum). A very small amount (~0.1%) is in the extracellular fluid. The normal plasma calcium concentration is around 2.4mM or 9.4mg/dL. Of this, around 50% is free ionised calcium, around 41% is bound to proteins, and around 9% is bound to anions.
Describe the mechanisms maintaining plasma [Ca2+]
Calcium is regulated through the calciostat system, which makes use of calcium-sensing receptors (CaSR). Various hormones (which I will discuss later) affect calcium absorption, reabsorption (in the kidneys), and resorption (from bone).
Calcium is very poorly absorbed. Roughly 30% of calcium is considered to be "absorbed," but when you consider the calcium in secretions and calcium in cells that are being sloughed off, we really only end up absorbing and using around 10% of the calcium that we eat. Absorption of supplemental calcium is even worse than absorption of calcium in food.
In the kidneys, ionised and anion-bound calcium are filtered, and then around 90% of it is constitutively reabsorbed in the proximal tubule and ascending Loop of Henle. The remaining 10% may also be absorbed in the distal tubule and collecting duct, but only under the influence of appropriate hormonal signals.
There are two main ways in which bone can be reabsorbed. The rapid method is called "osteocytic osteolysis." When calcium in the bone fluid decreases, mineralised bone solubility increases, causing release of more calcium into the bone fluid. Furthermore, if parathyroid hormone is circulating, it can bind to parathyroid receptors on osteoblasts, causing an increase in membrane permeability to calcium. Thus, parathyroid hormone binding causes an increase in Ca2+ release into the extracellular fluid. The slow method of bone resorption occurs via osteoclasts. They have a ruffled edge that increases their surface area. HCl and acid phosphatase (which breaks down collagen fibres) are released from this ruffled edge, breaking down bone and releasing calcium.
Discuss the hormonal control
There are three main hormones that control calcium levels: parathyroid hormone, vitamin D3, and calcitonin.
Parathyroid hormone (PTH)
PTH is released from the chief cells of the parathyroid glands (not to be confused with the chief cells of the stomach!). These chief cells have CaSR (calcium-sensing receptors) that, when activated, decrease PTH production and secretion. When calcium levels drop, CaSR are no longer activated, and PTH production and secretion increases. PTH causes an increase in calcium reabsorption and bone erosion, both of which increase plasma calcium levels.
Vitamin D3
As you should know, vitamin D is produced from 7-dehydrocholesterol after activation by UV light and a series of hydroxylations. Vitamin D3 can be produced in either an active (1, 25 D3) form or an inactive (24, 25 D3) form. The active form is only produced when parathyroid hormone is present; thus, parathyroid hormone can also indirectly cause an increase in calcium absorption.
Vitamin D3 increases calcium reabsorption in the kidneys and calcium absorption in the intestines, increasing calcium concentrations. D3 also increases calcification of bone, which decreases plasma calcium levels, but the decrease in calcium due to this process is dwarfed in comparison to the increase in calcium via reabsorption and absorption.
Insufficient vitamin D3 can cause rickets and osteomalacia. Rickets type II is a rare type of rickets in which the vitamin D receptor is mutated.
Calcitonin
Calcitonin is released by parafollicular cells in the thyroid gland. It is released when calcium levels are high. In contrast to PTH and D3, calcitonin decreases calcium levels. It does this by increasing calcium excretion and inhibiting the erosion of bone.
Discuss hypo- and hyperparathyroidism
Hypoparathyroidism
In hypoparathyroidism, there is insufficient secretion of PTH. This may be due to an autoimmune disease or due to loss of the parathyroids during thyroid removal. Insufficient PTH can cause hypocalcaemia, which is defined as a calcium level of less than around 6-7mg/dL. (Remember, normal calcium levels are around 9.4mg/dL). Since hypocalcaemia causes hyperexcitability, symptoms include muscle tetany (which results in a distinctive "Trousseau sign"), fatigue, headaches, tingling, seizures, bronchospasm, and cardiac arrhythmias.
Hyperparathyroidism
Hyperparathyroidism can be primary (usually due to a tumour of the parathyroid gland) or secondary (usually due to hypocalcaemia, which in turn can be due to rickets or chronic renal disease). Hyperparathyroidism causes excessive PTH secretion and excessive demineralisation of bone, leading to hypercalcaemia (defined as a calcium level greater than 12-15mg/dL). As high calcium causes cells to become less excitable, symptoms include depression of the CNS and PNS, muscle weakness, constipation, kidney stones (possibly due to precipitation of calcium salts), and coma.
Know the Ca2+ requirements and sources of Ca2+
See earlier post: Calcium and Phosphorous
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