calcium is crucial to all physiological function. It must be obtained from the diet, but since an intake of only about 1 g per day is adequate, shortage is rare; the net daily turnover (the absorption rate into blood, and excretion rate in the urine) is only about one-tenth of that amount again.
The average human body contains just over 1 kg of calcium, more than 99% of it in the
skeleton (and
teeth). Here it is mostly in the form of complex phosphate salts forming the rigid structures that allow bone to fulfil its essential supportive role. Skeletal calcium is not, however, inert. Bone contains cells that lay down new bone and resorb old bone and the regulated activities of these cells, made possible by the extensive blood supply that bone receives, ensure that skeletal calcium actively turns over. Beyond middle age, the rate of bone deposition fails to keep pace with its resorption and the disparity can become severe enough to cause
osteoporosis, when the bones become fragile and fracture easily. In addition to its structural role, the skeleton serves also as a reservoir from which calcium can be mobilized if necessary.
Calcium absorption from the small intestine and excretion from the
kidneys are also regulated to ensure that the concentration of calcium in the plasma is very precisely controlled, probably more tightly than any other component of plasma. The need for such precise calcium
homeostasis is underscored by the serious consequences that follow deviations from the norm. Excessively low plasma calcium levels (
hypocalcaemia) are particularly dangerous because they evoke spontaneous activity in both nerves and muscles, causing muscle spasms that can become so severe as to obstruct the airway. Conversely, with too high a plasma calcium level (
hypercalcaemia), nerves and muscle can become less active, leading to weakness. The longer term consequences of aberrant plasma calcium regulation can include skeletal problems and kidney stones.
Three agents are principally responsible for plasma calcium regulation, acting directly or indirectly at the three sites where the amount entering or leaving the blood can be influenced — bone, kidneys, and intestine.
Parathyroid hormone is a peptide released from the
parathyroid glands in the neck in direct response to any fall in the plasma calcium concentration. In bone it enhances calcium resorption and transfer into the blood. In the kidneys it both reduces calcium excretion and promotes formation of the active metabolite of vitamin D
3, which in turn enhances intestinal absorption. Thus parathyroid hormone helps to restore plasma calcium levels to normal.
Vitamin D (cholecalciferol) is not only a component of the diet (extra is added to cereals and dairy products) but also is synthesized in the skin in the presence of sunlight. After modification in the liver, vitamin D
3 is further modified to its active form in the kidneys, a step that is stimulated largely via parathyroid hormone, and hence in turn by a fall in the plasma calcium concentration. The active metabolite of vitamin D
3, 1,25-dihydroxycholecalciferol (
calcitriol) is a hormone that stimulates calcium uptake from the small intestine and mobilization of calcium from bone, both serving to reverse the fall in plasma calcium that triggered formation of the hormone initially. Defects in any of the pathways leading to formation of 1,25-dihydroxycholecalciferol give rise to
rickets.
Calcitonin is the third, and least important, calcium-regulating hormone. It is released from cells within the
thyroid gland in response to an increase in plasma calcium and to several other factors, including
gastrin, a hormone released during feeding and therefore heralding a potential rise in plasma calcium. Calcitonin serves to reverse any such rise by inhibiting bone resorption.
Clinical disorders of calcium regulation can arise for a variety of reasons, related not only directly to excess or deficiency of the relevant hormones, but also to conditions affecting kidney function and intestinal absorption; there can also be defects in the signalling proteins responsible for mediating the effects of parathyroid hormone on its target tissues. Conditions disturbing
acid–base homeostasis can alter the concentration of free calcium ions in the blood: alkalinity increases, and acidity decreases their binding to proteins in the plasma.
It is ironic that the insolubility of calcium phosphate that allows it to form so stable a structure in bone was probably also the ultimate cause, in evolutionary terms, of calcium coming to fulfil its other indispensible role as a dynamic regulator of cellular activity. The energy economy of every cell is now dominated by the transfer of phosphate groups, and since calcium phosphate is so insoluble, it is likely that cells have long (in evolutionary terms) been required to actively extrude calcium. Every cell now maintains a very low free calcium ion concentration in its cytoplasm, some 10 000 times or so lower than that in either the plasma or the enclosed calcium stores within the cell. These very steep calcium concentration gradients are maintained by using energy, generated from the metabolism of the cell, to actively export calcium from the cytoplasm, either out of the cell or into the internal stores. There are two benefits of this active calcium transport. Firstly, it allows the energy economy of the cell to operate free of the risk that the key intermediates will be precipitated by calcium. Secondly, it provides steep, ready-made gradients down which calcium can rapidly flow into the cytoplasm when appropriate physiological stimuli cause the opening of calcium
ion channels in either the plasma membrane or the membranes of the intracellular stores. Rigorously controlled leaking of calcium through such channels is ubiquitous in the regulation of cellular activity. The fertilization of an egg, every beat of the heart or contraction of any other muscle, release of transmitters from nerve endings — myriads of physiological responses — all are regulated by transient increases in cytoplasmic calcium ion concentration brought about by appropriate stimuli from outside the cell, that cause calcium channels to open, and allow movement down the gradient into the cell. The ensuing increase in cytoplasmic calcium concentration is detected by specific calcium-binding proteins, the most abundant of which is
calmodulin. The change in shape of these proteins that follows their binding of calcium allows them to interact specifically with their targets within the cell; these include enzymes, ion channels, and muscle fibres. The intense scrutiny to which calcium channels have been subjected in recent decades has revealed their structures and the stimuli that control their opening (which range from changes in voltage to extracellular and intracellular messenger molecules); it is also beginning to establish the molecular mechanisms underlying their behaviour. Despite the diversity of behaviours, one feature that appears to be shared by all calcium channels is their regulation by cytoplasmic calcium ion concentration itself: each seems to be subject to feedback inhibition by calcium, a mechanism that probably serves to prevent intracellular calcium from rising to levels that could be toxic. This function can fail in sick cells — an excessive influx of calcium is known for example to be destructive to neuronal function when brain cells are damaged by lack of oxygen.
As well as these crucial roles in cellular function and in bone, ionized calcium in the blood plasma is one of several factors necessary for the clotting process: its chemical removal by the addition of citrate solution allows donor blood to be kept fluid for transfusion.
C. W. Taylor
See also
blood;
body fluids;
cell;
ion channels;
neuromuscular junction;
parathyroid glands;
synapse.
