Calcitonin_ Video, Anatomy, Definition & Function _ Osmosis

NOTES 284 OSMOSIS.ORG CALCIUM & PHOSPHATE HORMONAL REGULATION CALCIUM & PHOSPHATE HOMEOSTASIS Blood calcium level regulation = Normal total blood calcium: 8.5-10mg/d| = Parathyroid hormone: 1 calcium level = Vitamin D: 1 calcium level = Calcitonin: | calcium level Extracellular calcium » Diffusible: can cross cell membranes = Free-ionized calcium (Ca?*): involved in cellular processes — neuronal action GENERALLY, WHAT IS 1T? potential, muscle contraction, hormone secretion, blood coagulation = Complexed calcium: Ca?* ionically bound to other negatively-charged molecules (e.g. oxalate, phosphate — electrically-neutral molecules, do not partake in cellular processes) = Non-diffusible: cannot cross cell membranes = Calcium bound to large negatively charged proteins (e.g. aloumin — protein-albumin complex too large to cross cell membranes — not involved in cellular processes) CALCITONIN osms.it/calcitonin CALCITONIN STRUCTURE = Polypeptide hormone involved in blood calcium regulation = Not primary calcium regulator, even if thyroid gland removed, remaining regulatory mechanisms able to maintain calcium homeostasis = Produced by thyroid gland’s parafollicular cells (C cells) = C cells synthesize preprocalcitonin (141 amino acid polypeptide) — successive enzymatic cleavage steps produces procalcitonin — immature calcitonin (33 amino acids) — mature calcitonin (32 amino acids) — stored/readied for release in secretory granules within C cells CALCITONIN RELEASE = Calcium-sensing receptors on C cells’ surface monitor blood calcium levels — if calcium drifts above normal range — calcitonin released CALCITONIN ACTION » | owers blood calcium level Bone = | bone resorption — | blood calcium concentration = WWhen attaching to bone matrix osteoclast membranes form multiple arms (ruffled border) — aids attachment, increases surface area — arms secrete acid — assists bone breakdown

Chapter 35 Endocrine Physiology: Calcium & Phosphate Hormonal Regulation = Calcitonin binds to calcitonin receptor Kidneys on basal osteoclast surface — G-protein = | calcium, phosphate reabsorption by coupled receptor activation — adenylate principal cells of distal convoluted tubules cyclase activation — adenosine triphosphate (ATP) converted to 3',5'- cyclic AMP (cAMP) — 1 cAMP levels — | number of osteocyte arms formed — | bone resorption FOLLICLES PARAFOLLICULAR CELLS (or C CELLS) _/ FOLLICULAR CELLS THYROID GLAND Figure 351 Calcitonin is made and stored in thyroid gland’s C cells. NORMALLY ... 0O 0 WHEN CALCITONIN BINDS ... G PROTEIN ADENYLATE CYCLASE ATP 1 cAMP BLOOD \ 0STEOCLAST V' BONE RESORPTION &—7— {' BLOOD CALCIUM 7 OSTEOCLAST Figure 35.2 When calcitonin binds to its receptor on an osteoclast, it reduces number of osteoclast arms formed, decreasing bone resorption and blood calcium. OSMOSIS.ORG 285

Chapter 35 Endocrine Physiology: Calcium & Phosphate Hormonal Regulation HIGH BLOOD CALCIUM LEVELS Cao?t ~O O G PROTEIN O -y / PHOSPHOLIPASE C CALCIUM - SENSING : \ RECEPTOR _AF | “ Q PTH release IS INHIBITED PARATHYROID d CELL N LOW BLOOD CALCIUM LEVELS \l/ Ca?* 7 | il g PTH gets RELEASED Figure 35.4 High calcium levels in blood inhibit PTH release from parathyroid cells, while low calcium levels in blood facilitate PTH release from parathyroid cells. Magnesium = Involved in stimulus-secretion coupling = Moderate | serum Mg?* concentration promotes action of PTH on renal mineral resorption = Severe hypomagnesemia (e.g. alcoholism) inhibits PTH secretion, causes PTH resistance EXTRACELLULAR CALCIUM INCREASE = PTH — 1 extracellular calcium levels (three target organ systems) Bones = PTH receptors on osteoblasts = PTH binding — 1 cytokine release = Receptor activator of nuclear factor kB ligand (RANKL) = Macrophage colony-stimulating factor (M-CSF) = Inhibits osteoprotegerin (OPG) secretion (inhibition absence — free OPG binds to RANKL (decoy receptor) — prevents RANK-RANKL interaction = PTH-induced cytokine release permits RANK-RANKL interaction — multiple macrophage precursors fuse — osteoclast formation (bone breakdown) = Bone breakdown — release of calcium, phosphate into blood (initially forms physiologically-inactive compound) Kidneys = PTH binds to receptors on cells of proximal convoluted tubules — inhibits sodium-phosphate co-transporters on apical surface — | sodium, phosphate reabsorption — 1 urinary phosphate excretion PTH binds to receptors on principal cells of distal convoluted tubules — sodium/ calcium channel upregulation — 1 calcium reabsorption from urine Intestines = PTH promotes vitamin Ds (cholecalciferol) conversion — active form = Cholecalciferol synthesized by keratinocytes in skin epidermis when exposed to UV light (also found in foods) — cholecalciferol travels to liver, enzyme 25-hydroxylase catalyzes conversion to 2b-hydroxycholecalciferol (calcidiol) = 25-hydroxycholecalciferol travels to kidney’s proximal tubular cells — enzyme 1-alpha-hydroxylase (upregulated by PTH) converts it to OSMOSIS.ORG 287

288 1,25-dihydroxycholecalciferol (calcitriol), AKA active vitamin D = Active vitamin D travels to gastrointestinal (Gl) tract — enterocytes of small intestine — upregulates calcium channels — 1 dietary calcium absorption COMPLEX CALCIUM OSTEOBLAST 'g g PTH BON * M-CSF OSTEOCLAST € RANKL FORMATION RANK-RANKL j INTERACTION <, \nc ROPHAGE PRECURSORS FUSE Figure 35.5 One way PTH increases extracellular calcium levels is by stimulating osteoclast formation in bone. coroxinaL - PARATHYROID HORMONE comoren TUBULE BINDS +o : TUBULE * TUBULAR CELLS: * PRINCIPAL CELLS: *{ ® [} L STOPS them REABSORBING L TUBULAR CELLS MAKE PHOSPHATE from URINE , k t Na* / Ca?* CHANNELS PHOSPHATURIA t Ca?*REABSORPTION from URINE Figure 35.6 The second way PTH increases extracellular calcium levels is by 1 urinary phosphate excretion and 1 calcium reabsorption from urine. OSMOSIS.ORG

290 OSMOSIS.ORG Ve D2 2 D3 PACKAGED with l i BILE SALTS into MICELLES ENTEROCYTES CHYLOMICRONS LYMPH <&t SMALL INTESTINE > BLOOD HEPATOCYTES CALCIFEDIOL ERCALCIDIOL LIVER B y K——) \ REENTER the BLOOD ENDOPLASMIC RETICULUM PROXIMAL TUBULE CELLS CALCIFEDIOL HO ERCALCIDIOL = - ~ ~ ~ 1c-HYDROXYLASE CALCITRIOL ERCALCITRIOL N~ ACTIVE VITAMIND MITOCHONDRIA KIDNEeYS Figure 35.8 Conversion of vitamins D, and D, into active vitamin D.

Chapter 35 Endocrine Physiology: Calcium & Phosphate Hormonal Regulation Alternative pathway Kidney = Hydroxylation at C24 — biologically = Stimulates Ca?*, phosphate reabsorption inactive 24,25-dihydroxycholecalciferol = Pathway choice regulated by blood calcium Intestine level, parathyroid hormone * Increases Ca*", phosphate absorption = C1 hydroxylation occurs as response to * Induces vitamin D-dependent Ca** binding- | calcium/phosphate levels protein synthesis (calbindin D-28K) s 1a-hydroxylase activity 1 through | = Systolic protein — binds four Ca** ions plasma Ca?" concentration, 1 circulating = Intestinal Ca®* absorption mechanism PTH levels, | plasma phosphate = Ca?* diffusion: intestinal lumen — cell concentration (through electrochemical gradient) s C1 phosphorylation requires NADPH, = |[nside cell: calbindin D-28K binds Ca?* O,, Mg**, cytochrome P-450 pathway — Ca?* pumped across basolateral o |f calcium levels sufficient, inactive membrane by Ca?*-ATPase metabolite preferentially produced VITAMIN D ACTIONS Bone = Acts synergistically with PTH — osteoclast activity stimulation — bone resorption — old bone demineralization — 1 Ca%, phosphate concentration for new bone mineralization OSTEOBLAST g VITAMIN D / OSTEOCLAST FORMATION RANK-RANKL INTERACTION MACROPHAGE PRECURSORS FUSE Figure 35.9 Vitamin D stimulates osteoclast formation, increasing blood calcium and phosphate concentrations. OSMOSIS.ORG 291