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PHYSIOLOGY OF MINERAL ION HOMEOSTASIS
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Elemental calcium is essential for a variety of biological functions. Its ionized form, Ca2+, is an important component of current flow across excitable membranes. Ca2+ is vital for muscle contraction, fusion, and release of storage vesicles. In the submicromolar range, intracellular Ca2+ acts as a critical second messenger (see Chapter 3). In extracellular fluid, millimolar concentrations of Ca2+ promote blood coagulation and support the formation and continuous remodeling of the skeleton.
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In the face of millimolar extracellular Ca2+, intracellular free Ca2+ is maintained at a low level, ~100 nM in cells in their basal state, by active extrusion by Ca2+–ATPases, by Na+/Ca2+ exchange, and by accumulation into cellular storage networks such as the sarcoplasmic reticulum. Changes in cytosolic Ca2+ (whether released from intracellular stores or entering via membrane Ca2+ channels) can modulate effector targets, often by interacting with the Ca2+-binding protein calmodulin. The rapid association–dissociation kinetics of Ca2+ and the relatively high affinity and selectivity of Ca2+-binding domains permit effective regulation of Ca2+ over the 100 nM to 1 μM range.
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The body content of calcium in healthy adult men and women, respectively, is ~1300 and 1000 g, of which >99% is in bone and teeth. Ca2+ in extracellular fluids is stringently regulated within narrow limits. In adult humans, the normal serum Ca2+ concentration ranges from 8.5-10.4 mg/dL (4.25-5.2 mEq/L, 2.1-2.6 mM) and includes 3 distinct chemical forms of Ca2+: ionized (50%), protein-bound (40%), and complexed (10%). Thus, whereas total plasma Ca2+ concentration is ~2.5 mM, the concentration of ionized Ca2+ in plasma is ~1.2 mM. The various pools of Ca2+ are illustrated schematically in Figure 44–1. Only diffusible Ca2+ (i.e., ionized plus complexed) can cross cell membranes. Albumin accounts for some 90% of the serum Ca2+ bound to plasma proteins; a change of plasma albumin concentration of 1.0 g/dL from the normal value of 4.0 g/dL can be expected to alter total Ca2+ concentration by ~0.8 mg/dL. The remaining 10% of the serum Ca2+ is complexed with small polyvalent anions, primarily phosphate and citrate. The degree of complex formation depends on the ambient pH and the concentrations of ionized Ca2+ and complexing anions. Ionized Ca2+ is the physiologically relevant component, mediates calcium's biological effects, and, when perturbed, produces the characteristic signs and symptoms of hypo- or hypercalcemia. The extracellular Ca2+ concentration is tightly controlled by hormones that affect calcium entry at the intestine and its exit at the kidney; when needed, these same hormones regulate withdrawal from the large skeletal reservoir.
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