Calcium Regulation & Parathyroid (U22201, P22180) Lecture Notes PDF

Calcium regulation & the parathyroid U22201, P22180 Dr. Sassan Hafizi  This lecture ¢CALCIUM REGULATION ¢ Other role players (Vitamin D, Calcitonin) PARATHYROID GLANDS ◦ Parathyroid hormone (PTH) ◦ Parathyroid diseases and treatment  CALCIUM Calciu...

Calcium regulation & the parathyroid U22201, P22180 Dr. Sassan Hafizi  This lecture ¢CALCIUM REGULATION ¢ Other role players (Vitamin D, Calcitonin) PARATHYROID GLANDS ◦ Parathyroid hormone (PTH) ◦ Parathyroid diseases and treatment  CALCIUM Calcium is an important ion! both inside and outside cell: ¢ Major component of bone ¢ ~50% bone weight (hydroxyapatite) ¢ 99% of Ca2+ in bone & teeth mineral  Calcium concentration control CYTOSOLIC [CA 2+ ] AT REST ~100 NM ~12,000-FOLD LOWER THAN EXTRACELLULAR [CA 2+ ] 2.2 - 2.55 mM CHANGED DUE TO ACTION OF PUMPS, ION CHANNELS, EXCHANGERS: In neurons, voltage-dependent Ca2+ channels (VDCC) important for synaptic transmission release neurotransmitters into synaptic cleft by synaptic vesicle fusion with PM ALSO, EXCHANGERS & PUMPS TRANSPORT CA 2+ OUT OF THE CELL  CALCIUM Calcium (Ca2+) is an important ion! ¢ Intracellular second messenger ¢ E.g. muscle contraction Calcium as 2nd messenger Ca2+ necessary for heart contraction (Ringer, 1883) Intracellular Ca2+ triggers muscle contraction (Heilbrunn, 1940s) Ca2+ activates contractile proteins (troponin-C, actin) and SR regulates intracellular Ca2+ (Ebashi, 1960s) Calmodulin - ubiquitous Ca2+-sensing protein (1973) Calcium as a signal molecule  Cytosolic calcium changes in signalling INCREASE IN CYTOSOLIC [CA 2+ ] (CA 20-FOLD) CAUSES: Fast signals - muscle contraction Sustained signals - transmitter secretion long-term changes - gene expression INTRACELLULAR CA 2+ STORED IN ENDOPLASMIC RETICULUM (ER) In muscle: sarcoplasmic reticulum (SR) Therefore, Ca2+ signalling is compartmentalised Signal varies due to amplitude, frequency shape Calcium “sparks”, “puffs”  CALCIUM Calcium (Ca2+) is an important ion! Ca2+ ions ¢ Needed for blood clotting ¢ Factors X, VII, IX, protein C etc. have crucial calcium-binding domains Calcium signalling in disease Ca2+ overload INSIDE cells - toxic ◦ Muscle contractile dysfunction ◦ eg heart failure ◦ Neurodegenerative processes ◦ Diabetic neuropathies ◦ Alzheimers (dementia) ◦ Disruption in ER Ca2+ homeostasis contributes to b amyloid synthesis Hypercalcaemia (high plasma [Ca2+]) ◦ Cardiac arrhythmia, lower neuromuscular transmission & jijs pres Hypocalcaemia (low [Ca2+]) ◦ Tetany, epilepsy, blood clotting problems  CALCIUM ¢ Extracellular [Ca2+] v. carefully regulated: — Normal : 2.2 - 2.55 mM ¢ Ca2+ exists in 3 forms: ¢ bound to albumin ¢ citrate complex ¢ free Ca2+ ion Calcium fluxes in the normal adult Bone Growth and Calcium Metabolism  BONE CELLS Osteoblasts - bone-forming cells ◦ Secrete osteoid (forms bone matrix) ◦ Also begin mineralisation Osteocytes - mature osteoblast ◦ No longer secretes matrix, but is surrounded by it ◦ Maintains metabolism, and participates in nutrient/waste exchange via blood Osteoclasts ◦ Function in resorption and degradation of existing bone ◦ opposite of osteoblasts ◦ Regulate Ca2+ release from bone  Osteoclast Releases H+ ions (proton pumps) into the resorptive cavity acidifies and dissolves mineralised bone matrix ◦ Release of Ca2+, H3PO4, H2CO3, water ◦ Hydrolytic enzymes also released, e.g. cathepsins, matrix metalloproteases (MMPs) ◦ digest organic components of the matrix  Osteoporosis Disease of bone growth & calcium metabolism Bone resorption exceeds deposition Factors: inadequate Ca2+ intake, genes, hormones, smoking Treatment: bisphosphonates ◦ inhibit activation of enzymes that utilise pyrophosphate Soluble factors (hormones) that affect calcium availability PARATHYROID GLANDS  Parathyroid ¢ 4 parathyroid glands ¢ Posterior to the thyroid, embedded in its lobes ¢ Each weighs 40-60mg ¢ Variations in no., size & location Histology of Parathyroid gland Chief cells ◦ Site of synthesis & secretion of: parathyroid hormone (PTH) Oxyphil cells ◦ Appear at puberty ◦ Larger size and smaller nucleus vs chief cells Summary of hormones by chemical class PTH - biosynthesis, storage & secretion Synthesised as the preprohormone (preproparathyroid hormone) by parathyroid gland chief cells Active form of PTH (84 aa peptide) is cleaved from the preprohormone before release from the gland Released by exocytosis in response to reduced plasma Ca2+ Synthesised continuously (degraded if not released) Secretion controlled by Vitamin D reduces PTH as a secondary mechanism (-ve feedback)  Biological activity of PTH OVERALL ACTION OF PTH IS TO: -INCREASE PLASMA Ca2+ LEVELS & -DECREASE PLASMA PHOSPHATE LEVELS BONE ◦ Direct effect ◦ Increases number and activity of osteoclasts ◦ Stimulates bone resorption ◦ releases Ca2+, phosphate into blood KIDNEY ◦ Causes ­ Ca2+ reabsorption & ­ phosphate excretion INTESTINE ◦ Stimulate vitamin D3 synthesis to increase Ca2+ reabsorption  Calcium regulation of PTH release Ca2+ is dominant regulator of plasma PTH secretion Parathyroid chief cell Continuous secretion ◦ rapid clearance (5 min) Maximum secretion of PTH occurs at plasma Ca2+ 90% cure  Hypoparathyroidism Far less common Causes hypocalcaemia and hyperphosphataemia – tetany, mental, eye PTH-deficient hypoparathyroidism ◦ Reduced or absent synthesis of PTH ◦ Often due to inadvertent removal of excessive parathyroid tissue during surgery (symptoms in 24-48h) PTH-ineffective hypoparathyroidism ◦ Synthesis of biologically inactive PTH PTH-resistant hypoparathyroidism (pseudohypoparathyroidism) ◦ PTH levels may be normal/high ◦ Due to congenital defect in PTH GPCR signalling (mutation in Gas subunit) ◦ Lack of normal response to administered PTH Treatment: Ca2+, Vit D (i.v. and oral), treat underlying cause OTHER CALCIUM-REGULATING HORMONES Vitamin D  Vitamin D synthesis Vitamin D obtained from sun (UV on skin), food, supplements Made from cholesterol ◦ Precursor is biologically inert ◦ must undergo two hydroxylation reactions to be activated ◦ via sequential enzymatic reactions in liver & kidney (stimulated by PTH) Ergocalciferol = vit D2; cholecalciferol = vit D3 Calcitriol = 1,25-hydroxycholecalciferol = 1,25-OH vit D3 - ACTIVE form of vitamin D3 in the body Alfacalcidol (analogue) = 1α-hydroxycholecalciferol = 1α-OH-vit D3  Vitamin D3 Carried by vitamin D-binding protein (VDBP) Binds to Vitamin D receptor (nuclear) Regulates genes that facilitate several important body functions: ◦ Stimulates intestinal calcium uptake ◦ Increases bone mineralisation ◦ Increases kidney phosphate uptake ◦ Also: Helps regulate thyroid and parathyroid function ◦ Modulates neuromuscular and immune function ◦ Reduces inflammation Vitamin D3 deficiency commonest cause of hypocalcaemia Synthesis, Release & Activity of Active Vitamin D PTH is elevated in Vitamin D deficiency Thomas, NEJM 1998 338:777 Calcium fluxes in the normal adult Vitamin D3= Calcitriol  Calcitonin 32-amino acid linear polypeptide hormone Synthesised and secreted by the parafollicular (“C”) cells of the thyroid Acts to decrease plasma Ca2+ levels ◦ (While PTH and vitamin D act to increase plasma Ca2+) ◦ is a physiological antagonist to PTH Target cell is the bone osteoclast ◦ Calcitonin inhibits osteoclast motility and cell shape ◦ Calcitonin effect: rapid fall in Ca2+ caused by inhibition of bone resorption Actions of thyroid hormones (prev. lecture) T3 & T4 cause: ◦ ↑ metabolic rate ◦ ↑ Protein synthesis ◦ ↑ breakdown of fats ◦ ↑ use of glucose for ATP production Calcitonin ◦ From the parafollicular cells Responsible for building of bone “C” cells Summary of hormones by chemical class Calcitonin Used clinically in treatment of hypercalcaemia (Salcatonin) ◦ & certain bone diseases in which sustained reduction of osteoclastic resorption is therapeutically advantageous (e.g. Paget’s disease) Calcitonin role in normal Ca2+ control is outweighed by PTH and Vitamin D3 ◦ May be more important in regulating bone remodelling than in Ca2+ homeostasis Calcium fluxes in the normal adult Roles of calcitriol, PTH and calcitonin in calcium homeostasis  1 High level of Ca2+ in blood 3 Low level of Ca2+ in blood stimulates thyroid gland stimulates parathyroid parafollicular cells to gland chief cells to release release more CT. more PTH. 6 CALCITRIOL stimulates increased absorption of Ca2+ from foods, which increases blood Ca2+ level. 5 PTH also stimulates the kidneys to release 4 PARATHYROID HORMONE (PTH) 2 CALCITONIN inhibits CALCITRIOL. promotes release of Ca2+ from osteoclasts, thus decreasing bone extracellular matrix into blood Ca2+ level. blood and slows loss of Ca2+ in urine, thus increasing blood Ca2+ level.  Calcium metabolism summary PTH & calcitonin release are regulated by plasma Ca2+ levels Bone serves as a ready reserve for maintenance of plasma Ca2+ levels Bone, kidney & intestine participate in the regulation of plasma [Ca2+ ] PTH, Vitamin D, & calcitonin balance plasma [Ca2+ ] for bone synthesis, muscle contraction, & cell signalling Endocrine diseases result from pathway or glandular hypo- or hypersecretion