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THE AUSTRALIAN NATIONAL UNIVERSITY

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Presentation on theme: "THE AUSTRALIAN NATIONAL UNIVERSITY"— Presentation transcript:

1 THE AUSTRALIAN NATIONAL UNIVERSITY
Calcium and Phosphate Homeostasis Christian Stricker Associate Professor for Systems Physiology ANUMS/JCSMR - ANU

2

3 Aims The students should
appreciate the physiological role of extracellular Ca2+; know the principles of storage of Ca2+ in different compartments; be able to explain the major factors determining extracellular Ca2+; recognize principles involved in Ca2+ and Pi homeostasis via hormones; understand how extracellular Ca2+ in sensed and signalled; and be able to distinguish differences between regulation of Ca2+ and Pi.

4 Contents Calcium (Ca2+) Phosphate (Pi) Notion of free and bound Ca2+
Extracellular versus intracellular Ca2+ Ca2+ exchanges (uptake → storage → excretion) Regulation of Ca2+ Short-term: pH and its consequences Long-term Nature of the Ca2+-sensor Hormonal control of Ca2+ homeostasis Phosphate (Pi) Free and bound Regulation of Pi

5 Total & “Free” Extracellular Ca2+
Non-filterable = protein bound (“albumin”) = cannot permeate through filter pores = non-diffusible = biologically not available (on normal time scale). Filterable = can permeate filter pores = diffusible; only some Ca2+ can be excreted. The absolute numbers might vary by a few percentages depending on source.

6 Extra- and Intracellular Ca2+

7 Ca2+ Balance Homeostasis is result of
uptake (absorption), deposition and resorption (bone), secretion and excretion, and exchange between ICF ↔ ISF. Ca2+ taken up in proximal part of small bowel (duodenum > jejunum). Excretion primarily via urine (kidney). Constant exchange between ICF and ISF as well as ISF and bone (no net change).

8 Exchange between ECF and ICF
Influx into cell via Ion channels Voltage-dependent, non-selective cation, store-operated and ligand-gated ion channels Transporters (reversed transport in pathology) Outflow via transporters Ca-ATPase Na/Ca-exchanger (3 Na+ against 1 Ca2+) Sequestration within cell Smooth endoplasmic reticulum Mitochondria Calcicosomes Fixed and soluble buffers (Ca2+-binding proteins)

9 Ca2+ Deposition and Resorption
Deposition/accretion via osteoblasts into bone Resorption via osteoclasts from bone Tightly controlled by hormones Guarantees a rapidly exchangeable pool (4 g out of recently made-up bone) Bone Inorganic minerals % Hydroxyapatite Organic part (matrix) % Collagen

10 Dietary Uptake Demand: 1 g / d 25 mmol / d
Demand dependent on age and gravidity Children: g / d Adolescent: g / d Pregnancy: g / d Lactation: g / d Resorption: %* *demand limited; also depends on Ca2+-complexes formed/presented in GI tract (oxalic acid, phytin) pH Source: Predominantly dairy products (milk, cheese, etc.)

11 Mechanism of Dietary Uptake
Boron/Boulpaep, 2003 Two pathways: Paracellular and transcellular. Paracellular: Uptake from ISF into blood via diffusion through vessel fenestrations. Transcellular: Requires a luminal Ca2+ channel and intracellular binding to a Ca2+-binding protein. Rate limiting step is into ISF; Ca-ATPase and/or Na/Ca-exchanger. Calcitriol (“vitamin D”) can speed up resorption rate (via protein expression).

12 Excretion of Ca2+ Kidney is organ for Ca2+ net- excretion.
Only 65% of Ca2+ can be filtered (“protein free” fraction). 98% of filtered Ca2+ resorbed. 2% of Ca2+ excreted. Mechanism of resorption is paracellular TAL (driven by voltage). transcellular Ca-ATPase Na/Ca-exchanger Resorption is hormonally controlled (see later).

13 Calcium Regulation Short-term: pH (faster than regulatory hormonal changes can act…) and its consequences. Long-term Ca2+ sensing on cell membrane. hormonal feedback-loops for Ca2+ homeostasis.

14 Short-Term Regulation
pH and Its Consequences

15 pH and [Ca2+]: Competition
Acidosis → total Ca2+↑: Ca2+ unbinds not only from plasma, but also from protein on endothelial membrane/sub-endothelial space (significant volume). pH also affects solubility products (Ca-phosphates, -carbonates, etc).

16 Effects of [Ca2+] Change
György’s formula for serum electrolytes: Describes qualitatively excitability of neuromuscular system; i.e. tendency for tetanic reactions (cramps). (tetanus = steady muscle contraction without distinct twitching) Examples: [K+]↑ (hyperkalaemia): tendency for tetanus since excitability increases (depolarisation of membrane potential). [Ca2+]↓ (hypocalcaemia): tendency for tetanus since excitability increases. [H+]↓ (alkalosis): tendency for tetanus since excitability increased (respiratory; i.e. during hyperventilation; double whammy since [Ca2+] also drops…).

17 Sensor of Extracellular [Ca2+] Hormonal Ca2+ Homeostasis
Long-Term Regulation Sensor of Extracellular [Ca2+] Hormonal Ca2+ Homeostasis

18 Ca2+- Sensor/Receptor (FREQ)
Gene on chromosome 9: Frequenin-like protein (FREQ) or NCS-1; GPCR – dimer. Binds to a host of adaptor proteins. Transduction pathways (incomplete) Phospholipases (C, A2, D): DAG, IP3 Adenylyl cyclase (inhibits) MAPKinase Regulated processes Secretion (hormones - relevant here…) Synaptic plasticity, memory formation Proliferation, differentiation, apoptosis Gene expression Diseases Rod and cone diseases (phosphorylation of rhodopsin) Up-regulated in bipolar disease and schizophrenia/autism

19 Parathyroid Hormone: [Ca2+]↑
Peptide (84 AA) from parathyroid gland Secretion “threshold”: < 1.5 mM (i.e. normally, very little PTH is secreted). Ca-sensor transduction: via phospholipase C → IP3 production AND adenylyl cyclase Target organs: Bone: osteoclasts (resorption) Kidney: accelerates vitamin D synthesis Indirectly: Gut, kidney (reabsorption, loss of phosphate…) Harper et al. 1979

20 Calcitriol: [Ca2+]↑ Lipophilic, steroid-like hormone
Synthesis involves 3 steps: Skin: Calciol Liver: 25-OH-cholecalciferol Kidney: Calcitriol Target organs: Primary: gut (uptake) Secondary: bone, kidney, placenta, breasts, hair follicles, skin, etc. Dosage: 5 µg/d adults; 10 µg/d children. Deficiencies: Inadequate dietary intake. Reduced absorption. Insufficient sun light exposure (England 19th century; kids/adults in front of computers, hospital beds, etc…). Reduced 1α-OH-ation (kidney disease). Despopoulos & Silbernagl 2003

21 Calcitonin: [Ca2+]↓ Peptide hormone (32 AA)
Secreted from C-cells in the thyroid gland. Secretion directly proportional to [Ca2+] (secreted when [Ca2+] normal). Ca-sensor transduction: via AC → cAMP. Target organs: Bone: inhibits osteoclast activity. Kidney: converts vit. D precursor to 24,25-(OH)2-cholecalciferol (inactive) → Ca2+ absorption↓. Harper et al. 1979

22 Ca2+- Regulation Overview

23 Phosphate (HPO42-; Pi) Largest amount intracellularly: ~ mM; ~ 200 g. Extracellularly, mostly as HPO42-; H2PO4- (Pi; 25%; pH!) Largest buffer in urine (some Pi always excreted). Reference range (plasma): 0.8 – 1.5 mM 85 – 90% filterable (Pi): 50% ionised; 50% complexed (Ca, Mg). 10 – 15% protein bound (as phosphorylation products). Less well regulated than Ca2+ (concentrations vary largely after food intake). Despite Ca/Pi supersaturation, no precipitation in tissue (pyrophosphate is one of many inhibitors of precipitation). Regulation tightly linked to Ca2+ because of bone (large deposit): hydroxyapatite, and Pi regulation is linked to PTH, calcitriol and calcitonin (little!).

24 Pi Balance Pi homeostasis is result of Mostly from dairy products.
amount of Pi in the body (bones); and distribution between ICF and ECF. Under normal conditions, Pi absorption = excretion (ss). Constant exchange between ICF and ECF as well as ECF and bone (no net change). Mostly from dairy products. Absorbed in proximal small bowel (duodenum > jejunum) by Na/Pi symporter. Excretion primarily via urine.

25 Targets of Pi Regulation
Regulation by maximal renal reabsorption capacity. Pi excess: rate of renal excretion↑; and Pi shortage: rate of renal excretion↓. Volume expansion response renal excretion↑ and vice versa. Primary targets (very similar to Ca2+) Kidney (80% reabsorbed in PT) Under normal conditions, Pi transport is saturated and matched to absorption: if Pi↑, more is lost than absorbed; if Pi↓, more Pi is retained. Low levels of Pi, alkalosis and hypercalcaemia cause insertion of Na/Pi symporter into apical membrane → reabsorption↑. High levels of Pi, acidosis and hypocalcaemia cause removal of Na/Pi symporter from apical membrane → reabsorption↓. Bone Resorption at the level of osteoclast (PTH, calcitriol) Formation at the level of osteoblast (calcitonin) Gut Enterocyte in duodenum/jejunum (calcitriol)

26 Pi Homeostasis PTH (most important): [Pi]↓ Calcitriol: [Pi]↑
increases bone resorption increases renal filtration Calcitriol: [Pi]↑ increases gut absorption increases renal reabsorption Calcitonin (transient; least important): [Pi]↓ increases bone formation Other hormones: growth hormone: Pi↑ in children glucocorticoids: Pi excretion↑ Not in line with Ca2+ homeostasis (more complex).

27 Take-Home Messages Ca2+ is central to extra- and intracellular signalling. [Ca2+]e determines excitability. [Ca2+] is sensed via FREQ (NCS-1), which requires adaptor protein(s) for transduction. Short-term, pH determines [Ca2+] and [Pi]. Hormones regulate [Ca2+] and [Pi]: PTH: [Ca2+]↑ and [Pi]↓. Calcitriol (vit. D): [Ca2+]↑ and [Pi]↑ via uptake↑ and also [Pi]↑ via renal reabsorption↑. Calcitonin: [Ca2+]↓ and [Pi]↓.

28 MCQ John Mak, a 58 year-old male, was diagnosed with prostate cancer and multiple osteolytic lesions causing markedly increased serum calcium. Which of the following statements best describes the accompanying blood Pi concentration? Normal independent of calcium concentration Elevated dependent on calcium concentration Lowered dependent on calcium concentration Lowered independent of calcium concentration Elevated independent of calcium concentration

29 That’s it folks…

30 MCQ John Mak, a 58 year-old male, was diagnosed with prostate cancer and multiple osteolytic lesions causing markedly increased serum calcium. Which of the following statements best describes the accompanying blood Pi concentration? Normal independent of calcium concentration Elevated dependent on calcium concentration Lowered dependent on calcium concentration Lowered independent of calcium concentration Elevated independent of calcium concentration


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