Calcium Absorption and Secretion Dietary Ca is absorbed in two ways: • Active transcellular pathway: via the TRPV6 (transient receptor potential vanilloid 6) channel on the apical membrane of the duodenum and proximal jejunum mucosa • Paracellular Ca transport: occurs through entire intestine Absorption: • Calcitrol is needed for Ca absorption. Ca will then go on to form insoluble salts (calcium phosphate and calcium oxalate) • 1000mg/day ingested  400-500mg absorbed  300mg lost in stool via digestive secretions  net absorption: 100-200mg/day Bone Calcium • Most of the body’s calcium and phosphate exists in the body as hydroxyapatite • The bones act as a reservoir to maintain plasma a concentrations o This process depends on osteoblast and osteoclast activity o This is regulated by many hormones and proteins including PTH and calcitriol Renal Handling • Only free/ionized Ca is filtered by the glomerulus • 97-99% of tubular Ca is reabsorbed o 70% passively via Na reabsorption in PCT o 20% passively via paracellular mechanisms in TAL  Mediated by claudin-16 (± claudin-19) channel for divalent cation reabsorption  Lumen-positive potential generated by backflux of K and Na from cells of TAL to lumen is major driving force o 10-15% actively via transcellular mechanism in distal nephron  Responsible for physiologic Ca regulation Calcium Regulation Parathyroid Hormone (PTH) (1 of 2 Regulators) • PTH is a polypeptide secreted in response to decrease in plasma ionized Ca • Ca sensing receptors (CaSR) on parathyroid cells detect calcium and alters PTH secretion accordingly • Polymorphisms in CaSR lead to variability in Ca levels in individuals • Inactivating mutations in CaSR  hypercalcaemia because higher Ca levels in blood is needed to activate CaSR and thus supress PTH release • Ca regulates PTH production, release and degradation in all of PTH’s molecular forms • Synthesis: o Pre-pro-PTH (115 amino acid polypeptide) produced o Cleaved in PT cells at N-terminal portion to become proPTH (90 amino acid polypeptide) o Cleaved again into PTH (84 amino acid polypeptide) (biologically active) o N-terminal cleaved pre-sequence is rich in hydrophobic amino acids necessary for transport into endoplasmic reticulum o Pro-peptide directs accurate cleavage of pro-PTH into PTH o C-terminal of PTH needed for PTH secretion by exocytosis within seconds of hypocalcaemia o In hypocalcaemia, intracellular PTH degradation decreases and biologically active PTH 1-84 is secreted o In hypercalcaemia, mostly biologically inactive Cterminal fragments secreted (PTH 7-84) • 5-30% intact PTH • 70-95% C-terminal fragments • Very small % N-terminal fragments • PRH is rapidly cleared through liver and kidney uptake. PTH 184 is cleaved and N- and C- terminal fragments are cleared by the kidney o iPTH half-life: 2-4min o C-terminal fragments half-life: 20-40min • PTH response to hypocalcaemia o Seconds to minutes: exocytosis of PTH from secretory vesicles into ECF o Minutes to 1 hour: ↓ intracellular PTH degradation o Hours to days: ↑PTH gene expression o Days to weeks: PT cells proliferation  This is also stimulated by low serum calcitriol