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CS 2014 Calcium and Phosphate Homeostasis Christian Stricker Associate Professor for Systems Physiology ANUMS/JCSMR - ANU

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Presentation on theme: "CS 2014 Calcium and Phosphate Homeostasis Christian Stricker Associate Professor for Systems Physiology ANUMS/JCSMR - ANU"— Presentation transcript:

1 CS 2014 Calcium and Phosphate Homeostasis Christian Stricker Associate Professor for Systems Physiology ANUMS/JCSMR - ANU THE AUSTRALIAN NATIONAL UNIVERSITY

2 CS 2014

3 Aims The students should appreciate the physiological role of extracellular Ca 2+ ; know the principles of storage of Ca 2+ in different compartments; be able to explain the major factors determining extracellular Ca 2+ ; recognize principles involved in Ca 2+ and P i homeostasis via hormones; understand how extracellular Ca 2+ in sensed and signalled; and be able to distinguish differences between regulation of Ca 2+ and P i.

4 CS 2014 Contents Calcium (Ca 2+ ) –Notion of free and bound Ca 2+ –Extracellular versus intracellular Ca 2+ –Ca 2+ exchanges (uptake → storage → excretion) –Regulation of Ca 2+ Short-term: pH and its consequences Long-term –Nature of the Ca 2+ -sensor –Hormonal control of Ca 2+ homeostasis Phosphate (P i ) –Free and bound –Regulation of P i

5 CS 2014 Total & “Free” Extracellular Ca 2+ 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 Ca 2+ can be excreted. The absolute numbers might vary by a few percentages depending on source.

6 CS 2014 Extra- and Intracellular Ca 2+

7 CS 2014 Ca 2+ Balance Homeostasis is result of –uptake (absorption), –deposition and resorption (bone), –secretion and excretion, and –exchange between ICF ↔ ISF. Ca 2+ 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 CS 2014 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 Ca 2+ ) Sequestration within cell –Smooth endoplasmic reticulum –Mitochondria –Calcicosomes –Fixed and soluble buffers (Ca 2+ -binding proteins)

9 CS 2014 Ca 2+ 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 70% Hydroxyapatite –Organic part (matrix) 30% Collagen

10 CS 2014 Dietary Uptake Demand: 1 g / d 25 mmol / d Demand dependent on age and gravidity –Children: 1.2 g / d –Adolescent: 1.0 g / d –Pregnancy: g / d –Lactation: g / d Resorption: %* *demand limited; –also depends on Ca 2+ -complexes formed/presented in GI tract (oxalic acid, phytin) –pH Source: –Predominantly dairy products (milk, cheese, etc.)

11 CS 2014 Mechanism of Dietary Uptake Two pathways: Paracellular and transcellular. Paracellular: Uptake from ISF into blood via diffusion through vessel fenestrations. Transcellular: –Requires a luminal Ca 2+ channel and intracellular binding to a Ca 2+ -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). Boron/Boulpaep, 2003

12 CS 2014 Excretion of Ca 2+ Kidney is organ for Ca 2+ net- excretion. Only 65% of Ca 2+ can be filtered (“protein free” fraction). 98% of filtered Ca 2+ resorbed. 2% of Ca 2+ excreted. Mechanism of resorption is –paracellular TAL (driven by voltage). –transcellular Ca-ATPase Na/Ca-exchanger Resorption is hormonally controlled (see later).

13 CS 2014 Calcium Regulation Short-term: pH (faster than regulatory hormonal changes can act…) and its consequences. Long-term –Ca 2+ sensing on cell membrane. –hormonal feedback-loops for Ca 2+ homeostasis.

14 CS 2014 Short-Term Regulation pH and Its Consequences

15 CS 2014 pH and [Ca 2+ ]: Competition Acidosis → total Ca 2+ ↑: Ca 2+ 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 CS 2014 Effects of [Ca 2+ ] 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). –[Ca 2+ ] ↓ (hypocalcaemia): tendency for tetanus since excitability increases. –[H + ] ↓ (alkalosis): tendency for tetanus since excitability increased (respiratory; i.e. during hyperventilation; double whammy since [Ca 2+ ] also drops…).

17 CS 2014 Long-Term Regulation Sensor of Extracellular [Ca 2+ ] Hormonal Ca 2+ Homeostasis

18 CS Ca 2+ - 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, A 2, D): DAG, IP 3 –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 CS 2014 Parathyroid Hormone: [Ca 2+ ]↑ 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 → IP 3 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 CS 2014 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 19 th century; kids/adults in front of computers, hospital beds, etc…). –Reduced 1α-OH-ation (kidney disease). Calcitriol: [Ca 2+ ]↑ Despopoulos & Silbernagl 2003

21 CS 2014 Calcitonin: [Ca 2+ ]↓ Peptide hormone (32 AA) Secreted from C-cells in the thyroid gland. Secretion directly proportional to [Ca 2+ ] (secreted when [Ca 2+ ] 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) → Ca 2+ absorption↓. Harper et al. 1979

22 CS 2014 Ca 2+ - Regulation Overview

23 CS 2014 Phosphate (HPO 4 2- ; P i ) Largest amount intracellularly: ~ mM; ~ 200 g. Extracellularly, mostly as HPO 4 2- ; H 2 PO 4 - (P i ; 25%; pH!) –Largest buffer in urine (some P i always excreted). Reference range (plasma): 0.8 – 1.5 mM –85 – 90% filterable (P i ): 50% ionised; 50% complexed (Ca, Mg). –10 – 15% protein bound (as phosphorylation products). Less well regulated than Ca 2+ (concentrations vary largely after food intake). Despite Ca/P i supersaturation, no precipitation in tissue (pyrophosphate is one of many inhibitors of precipitation). Regulation tightly linked to Ca 2+ because –of bone (large deposit): hydroxyapatite, and –P i regulation is linked to PTH, calcitriol and calcitonin (little!).

24 CS 2014 P i Balance P i homeostasis is result of –amount of P i in the body (bones); and –distribution between ICF and ECF. –Under normal conditions, P i 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/P i symporter. Excretion primarily via urine.

25 CS 2014 Targets of P i Regulation Regulation by maximal renal reabsorption capacity. –P i excess: rate of renal excretion↑; and –P i shortage: rate of renal excretion↓. –Volume expansion response renal excretion↑ and vice versa. Primary targets (very similar to Ca 2+ ) –Kidney (80% reabsorbed in PT) Under normal conditions, P i transport is saturated and matched to absorption: if P i ↑, more is lost than absorbed; if P i ↓, more P i is retained. Low levels of P i, alkalosis and hypercalcaemia cause insertion of Na/P i symporter into apical membrane → reabsorption↑. High levels of P i, acidosis and hypocalcaemia cause removal of Na/P i 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 CS 2014 P i Homeostasis PTH (most important): [P i ]↓ –increases bone resorption –increases renal filtration Calcitriol: [P i ]↑ –increases gut absorption –increases bone resorption –increases renal reabsorption Calcitonin ( transient; least important ): [Pi]↓ –increases bone formation –increases renal filtration Other hormones: –growth hormone: P i ↑ in children –glucocorticoids: P i excretion↑ Not in line with Ca 2+ homeostasis (more complex).

27 CS 2014 Take-Home Messages Ca 2+ is central to extra- and intracellular signalling. [Ca 2+ ] e determines excitability. [Ca 2+ ] is sensed via FREQ (NCS-1), which requires adaptor protein(s) for transduction. Short-term, pH determines [Ca 2+ ] and [P i ]. Hormones regulate [Ca 2+ ] and [P i ]: –PTH: [Ca 2+ ]↑ and [P i ]↓. –Calcitriol (vit. D): [Ca 2+ ]↑ and [P i ]↑ via uptake↑ and also [P i ]↑ via renal reabsorption↑. –Calcitonin: [Ca 2+ ]↓ and [P i ]↓.

28 CS 2014 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 P i concentration? A.Normal independent of calcium concentration B.Elevated dependent on calcium concentration C.Lowered dependent on calcium concentration D.Lowered independent of calcium concentration E.Elevated independent of calcium concentration

29 CS 2014 That’s it folks…

30 CS 2014 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 P i concentration? A.Normal independent of calcium concentration B.Elevated dependent on calcium concentration C.Lowered dependent on calcium concentration D.Lowered independent of calcium concentration E.Elevated independent of calcium concentration


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