D, Calcitriol, and Calbindins

Vitamin D is a fat soluble vitamin derived from cholesterol. In the human epidermis (skin), sunlight spontaneously oxidizes cholesterol to 7-dehydrocholesterol (Fig. 10.10a). The 7-dehydrocholesterol leaks into the blood where it isomerizes to cholecalciferol (vitamin D3, Fig. 10.10b and c). Cholecalciferol is enzymatically hydroxylated at C25 in the liver (25-cholecalciferol) and then passes to the kidney where another enzyme is activated by parathyroid hormone to hydroxylate it at Cl, forming calcitriol (Fig. lO.lOd). The kidney hydroxylase is sensitive to feedback inhibition. As the amount of calcitriol increases, it binds to the hydroxylase and alters the specificity of the kidney enzyme. Additional 25-cholecal-ciferol is hydroxylated to 24,25-dihydroxycholecalciferol (inactive calcitriol) instead of 1,25 dihydroxycholecalciferol (calcitriol). Other vitamin D derivatives that can be converted to calcitriol are obtained enzymatically from cholesterol in other vertebrates. The most common of these are vitamin D3 (lamisterol) and D2 (ergosterol) from cold-water fish such as cod, where their presence keeps membranes fluid at low body temperatures 10-20°C. 

Calcitriol behaves like a steroid hormone. It is transported to the nucleus of renal distal tubule cells, intestinal epithelial cells, osteoclasts, and osteoblasts where it induces calbindins, vitamin D-dependent calcium binding proteins. Calbindins mediate the intracellular movement of calcium, from diet to blood, from blood to osteoid matrix, or from bone to blood. There are two calbindin proteins, each encoded by separate genes, one of molecular weight about 9 kDa (calbindin-D. ) and one of molecular weight 28 kDa (calbindin-D28K). Each binds micromolar amounts of calcium and each disappears from animals that are 

Alternative hydroxylation at C24 in the kidney, inactive calcitriol. (Occurs when PTH is low or calcitriol is adequate) 

Vitamin D-mediated transcellular calcium transport also involves entry and extmsion. Calcium influx from the intestine or bone is propelled by a steep electrochemical gradient mediated by the superfamily of Transient Receptor Potential (TRP) ion channels noted above. TRP channel ion selectivity and mode of activation are extremely variable. Some are activated or regulated by ligands such as amino acid amines or small peptides, others by physical stimuli (e.g., heat), and still others by as yet unknown mechanisms. All TRP channels are Ca2+ and Na+ selective, but the selectivity for Ca2+ versus Na+ (Ca/Na ratio) varies enormously from 100 1, to 0.05 1. This variability has contributed to a confusing TRP channel nomenclature. 

---