Control Of Plasma
Calcium
In cells, Ca2+ ions are used to trigger many key
physiological events, including
muscle contraction (Chapter 12), the release of neurotransmitters (Chapter 7),
the release of hormones (Chapters 43 and 44), secretion from exocrine glands
and the activation of many important intracellular enzymes, such as the
calcium-calmodulin kinases (CAM kinases) (Chapter 46) and nitric oxide synthase
(Chapters 21 and 51). Ca2+ ions are triggers in so many crucial
events that free intracellular Ca2+ must be maintained at a very low
level (Chapter 2). Most is stored in the endoplasmic reticulum or mitochondria.
External to cells, Ca2+ ions contribute to the blood clotting
cascade (Chapter 9) and the normal functioning of Na+ ion channels (Chapter 4).
When extracellular Ca2+ is too low, Na+ channels open
spontaneously, leading to involuntary contractions of skeletal muscles,
described as hypocalcaemic tetany. This is the clinical sign of low
plasma Ca2+. It is evident that Ca2+ levels in plasma
must be very carefully controlled, a function performed by the coordinated activity
of three hormones: parathyroid hormone (PTH), 1,25-dihydroxycholecalciferol
[1,25-(OH)2D] and calcitonin (Fig. 48a).
Parathyroid hormone and
calcitonin
PTH, a peptide of 84 amino acids, is the major
controller of free calcium in the body. It is released from chief cells of
the four (or more) parathyroid glands located immediately behind the
thyroid gland, when the plasma concentration of Ca2+ decreases. The
ion is detected by a membrane-bound receptor protein expressed by chief cells.
When Ca2+ ions bind to the receptor, intracellular levels of cyclic
adenosine monophosphate (cAMP) (Chapter 3) decrease and the release of PTH is inhibited.
PTH increases the plasma levels of Ca2+ by activating specific
membrane receptors in bone, gut and kidney. In bone, the immediate effect of
PTH is to stimulate osteocytic osteolysis of bone crystals to release Ca2+
ions (Chapter 47). After a longer time, PTH also increases osteoclast activity
(Chapter 47) to gain access to more of the bone mineral. In the gut, PTH,
acting in concert with 1,25-dihydrocholecalciferol, enhances the absorption of
Ca2+ ions. In the kidney, the same combination of hormones enhances
the reabsorption of Ca2+ from the renal tubules and simultaneously
decreases the reabsorption 3−
of PO4 ions (Chapter 34). PTH also stimulates the kidney to produce more 1,25-dihydrocholecalciferol. Thus, PTH
leads the response to a fall in plasma Ca2+ by releasing ions stored
in bone, conserving ions filtered by the kidney and enhancing the intake of new
ions from the gut (Fig. 48a). The effects of PTH are in each case mediated by stimulating
an increase in cAMP in the target cells. Calcitonin is a 32-amino acid
peptide released from C cells of the thyroid gland in response to high levels
of plasma Ca2+ ions. C cells carry the same Ca2+ receptor
as parathyroid chief cells. Calcitonin inhibits bone resorption by osteocytes
and may inhibit reabsorption in the kidney, so reducing plasma levels of the ion. The fact that complete
removal of the thyroid gland causes
no obvious problems with calcium homeostasis has led some physiologists to
doubt the significance of this hormone in the normal control of Ca2+ ions.
Vitamin D and 1,25-dihydroxycholecalciferol
Vitamin D is an umbrella term for
two molecules: ergocalciferol (vitamin D2) and cholecalciferol (vitamin
D3). Both are derivatives of provitamin D (dehydrocholesterol; Fig. 48b) and
the primary source of supply is the diet, with ergocalciferol derived from
plants and yeasts and cholecalciferol from animal (particularly dairy)
products. Unusually for a vitamin, cholecalciferol can be manufactured within
the body via a reaction that is enabled by ultraviolet irradiation of the skin.
The D vitamins are then converted to 1,25-dihydroxycholecalciferol in the
kidney (Fig. 48b). The final reaction is the slowest step in the process and
therefore regulates the speed of the entire chain of reactions (i.e. it is rate
limiting); it is under the influence of PTH. 1,25-Dihydroxycholecalciferol has
a steroid-like structure and is sometimes referred to as a sterol. Its
receptors are members of the superfamily of steroid receptors and are located inside
target cells. The hormone–receptor complex binds to response elements on
deoxyribonucleic acid (DNA) to drive the transcription of genes. Calcium-
binding protein, which is thought to promote calcium transport across
epithelia (Chapter 34), is the product of one of the genes activated by
1,25-dihydroxycholecalciferol. The major action of 1,25-dihydroxycholecalciferol
is to enable Ca2+ absorption from the gut. Without the hormone, Ca2+
uptake is severely impaired to the point at which intake of the hormone is
insufficient to maintain body stores. This leads to the increased release of
PTH and resorption of bone. A lack of D vitamins in children leads to
inadequate calcification of bones, which become malformed. This leads to the
characteristically bowed limbs seen in rickets. This condition was
common in the early part of the 20th century, but was virtually eliminated in
the UK by the introduction of free school milk. Insufficiency of vitamin D in
adults leads to bone wasting, a condition known as osteomalacia, with
symptoms similar to those of
osteoporosis (Chapter 47). 1,25-Dihydroxychole calciferol also promotes the
reabsorption of Ca2+ from the kidney tubules. The effects of this
hormone are generally augmented in the presence of PTH.
Other hormones affecting calcium
Growth-promoting hormones (growth
hormone, thyroid hormones and sex steroids) tend to promote the incorporation
of calcium into bones (Chapter 47). Excess
corticosteroids (Chapter 49)
inhibit calcium uptake from the gut and reabsorption from the
kidney.
