Hormonal control of calcium homeostasis Chapter 9

 Calcium

• Adult human body has ~ 1000 g calcium

• 99% of total body calcium resides in bone

• 1% is exchanged with the extracellular fluid

• Extracellular calcium is used for biomineralization, cofactors for enzymes (e.g. in coagulation cascade),
membrane function and as a hormone

• Intracellular calcium is used for controlling secretion, cell division and as mediators of hormone action

• Calcium is mainly derived from diet

• 50% of total calcium in the blood is bound to proteins (albumin & globulin)

• Ionized (free) calcium ~ 1.2 mM is biologically active and tightly regulated

• Hypocalcemia increases the excitability of cell membranes

• Hypercalcemia causes neuromuscular suppression, dehydration, weight loss

• Cytosolic calcium concentration ~ 0.1 μM, whereas the extracellular concentration is ~ 1.2 mM

• Low cytosolic calcium concentration is maintained by Ca 2+/H+ -ATPases and by low affinity Na+/Ca2+
exchangers

• 99% of the intracellular calcium is associated with ER, mitochondria and the plasma membrane

 Calcium ion homeostasis

• Requires the activity of two hormones parathyroid hormone (PTH) and 1α, 25-dihydroxycholecalciferol
[1,25 (OH)2 D3] or calcitriol

• In lower vertebrates, in a marine environment calcitonin is important

• PTH, calcitriol, calcitonin are “calcitropic” hormones

 Parathyroid glands

• Embedded on the surface of the thyroid gland

• In humans, 4 parathyroid glands (two in each lobe)

• Two main cell types: chief or principal cells (produce PTH) and oxyphil cells (function unknown)

• Chief cells synthesize large amounts of PTH in a regulated manner

• Secrete PTH in response to changes in blood calcium concentrations

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• Parathyroid glands can replicate if they are chronically stimulated

• Removal of the parathyroid gland is lethal

 Parathyroid hormone (PTH)

• Straight chain polypeptide (84 aa)

• Controls minute-to-minute concentrations of calcium in the bloodstream

• Promotes the transfer of calcium from bones, renal tubules and intestine into the extracellular fluid

• Promotes the transport of calcium and phosphate indirectly by stimulating synthesis of 1,25(OH) 2D3

 PTH synthesis

• preproPTH (115 aa) → proPTH (90 aa) → PTH (84 aa)

• PTH packaged into secretory vesicles together with cathepsin

• When plasma calcium levels are high, cathepsin-mediated cleavage of PTH is accelerated

• C-terminal PTH fragments are inactive but persist in the blood for much longer than intact PTH

 Regulation of the PTH gene and PTH cell number

• Under hypercalcemic conditions → accelerated degradation of PTH

• Over long-term: 1,25(OH)2D3 suppresses PTH gene transcription; hypocalcemia increases PTH mRNA
synthesis; hypercalcemia has little or no effect on PTH mRNA levels

• Low calcium, low 1,25(OH)2D3, and hyperphosphatemia → increase PTG cell number

 Control of PTH secretion

• Major regulator is plasma calcium concentration which acts

through a calcium-sensing receptor (a GPCR)

• Chief cells synthesize and secrete PTH constitutively unless

inhibited by increases in extracellular calcium

• Calcium-sensing receptor on chief cells is coupled to both Gi

and Gq

• Increases in plasma calcium leads to a decrease in

intracellular cAMP and increase in calcium

 Bone
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• Specialized connective tissue with a mineralized matrix

• Continually being remodelled

• Two types of bone: compact bone (dense) & spongy bone (trabecular or cancellous)

• Bone matrix consists of: organic matrix (~35%) composed primarily of collagen and inorganic salts (~
65%) composed of hydroxyapatite crystals

 Bone cells (4 types)

• Osteoprogenitor cells (precursor cells)Give rise to osteocytes

• Osteoblasts Secrete collagen & ground substance (non-mineralized)

• Osteocytes Mature bone cells that develop from osteoblasts

• Osteoclasts Involved in bone resorption & rest directly on surfaces being remodelled

 Physiological actions of PTH on bone

• PTH stimulates the mobilization of calcium phosphate from the bone matrix

• Mobilization of calcium is mainly due to enhanced osteoclastic activity

 Physiological actions of PTH on kidney

• PTH enhances calcium reabsorption (uptake) at the luminal surface & calcium extrusion at the basolateral
surface

• PTH inhibits reabsorption of phosphate

• PTH receptor activation results in the phosphorylation of NERF (Na+-H+ exchange regulatory factor) and
releases PT (Phosphate-sodium co-transporter) from the plasma membrane

• PTH enhances internalization & degradation of PT

• PTH stimulates hydroxylase activity resulting in the formation of 1,25 (OH) 2 D3

 Vitamin D-Endocrine System

• Vitamin D is not a vitamin but a precursor for steroid-like compounds

• 1,25 dihydroxycholecalciferol [1,25(OH) 2D3] or calcitriol is necessary for calcium homeostasis & bone
mineralization

• Vitamin D deficiency results in osteomalacia

 Vitamin D-Endocrine System

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• Vitamin D3 is synthesized endogenously from 7-dehydrocholesterol (7-DHC) in the skin

• 7-DHC undergoes photo-isomerization to form previtamin D 3 which then undergoes thermal

isomerization to form cholecalciferol (Vit D3)

• Cholecalciferol is secreted from the skin into the bloodstream & transported by a binding protein to the
liver

• Hydroxylations occur in the liver, then in the kidneys to produce 1,25(OH) 2D3 which is biologically active

 Mechanism of action of 1,25(OH) 2D3

 Physiological
actions of
1,25(OH)2D3
on the
intestine

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 1,25 (OH)D increases transcription of mRNA for epithelial calcium channels (ECaC), calcium –binding
proteins (CaB), sodium-phosphate cotransporter, Ca 2+ -ATPase, and Na+/Ca2+-exchanger

 Physiological actions of 1,25(OH)2D3 on the intestine

 1,25 (OH)D increases transcription of mRNA for epithelial calcium channels (ECaC), calcium –binding
proteins (CaB), sodium-phosphate cotransporter, Ca 2+ -ATPase, and Na+/Ca2+-exchanger
 Physiological actions of 1,25(OH)2D3 on other tissues
 Increases reabsorption of calcium & phosphate in the kidney distal tubule
 Exerts negative feedback on the synthesis of PTH (direct and indirect)

 Regulation of 1,25(OH)2D3 production

• PTH increases synthesis of 1,25(OH)2D3

• PTH increases the expression of renal1α-hydroxylase (rate-limiting step)

• 1,25(OH)2D3 inhibits its own production via a short-feedback loop by downregulating 1α-hydroxylase

• 1,25(OH)2D3 upregulates enzymes involved in the inactivation of Vit D 3

• Direct and indirect effects of plasma calcium & phosphate

 Parathyroid hormone-related peptide (PTH-rP)

• Produced in a wide variety of tissues

• Very little PTH-rP circulating in blood (except in lactating females)

• 139-173 aa peptide (depending on the species)

• High degree of N-terminal homology with PTH

• Capable of activating the PTH receptor in bone and kidney

• Hypersecretion occurs in some types of tumour cells

 Parathyroid hormone-related peptide (PTH-rP) functions

• May have functions unrelated to calcium metabolism

• Causes relaxation of smooth muscle

• Stimulates chondrocyte growth and differentiation

• Increases the placental uptake of calcium from the maternal circulation

 Calcitonin (CT)

• Produced in the parafollicular cells (C-cells) of the thyroid gland

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• In non-mammalian vertebrates, CT is produced in ultimobranchial glands

 Calcitonin synthesis

• The CT gene also encodes for a structurally similar peptide called calcitonin gene-related peptide (CGRP)

• CGRP mainly produced in the nervous system

• CT gene has six exons but only the first four are used

• Alternative splicing of RNA transcript leads to tissue-specific expression of CGRP

• CT and CGRP exert their effects through distinct receptors

 Calcitonin secretion

• Circulating CT is normally very low

• Elevated plasma calcium increases CT secretion

• C-cells possess a calcium-sensing receptor like the parathyroid cells

• Response to elevated calcium is greater in males than females

• CT secretion shows age-related decline which correlates to the decline in gonadal function

• Infusion of calcium into pig stomach without causing detectable hypercalcemia causes a seven-fold
increase in circulating CT

• Gastrin (a GI tract hormone) stimulates CT secretion

• Gastrin analogs show a potency profile similar in their ability to stimulate gastric acid secretion

• Some patients with Zollinger-Ellison disease (hypergastrinemia) have elevated levels of CT

 Physiological actions of calcitonin

• CT is not essential for calcium homeostasis in humans- no obvious pathological symptoms of CT

deficiency or excessive production

• CT lowers blood calcium levels by acting on bone and the kidney

• In bone, CT inhibits osteoclast activity via an elevation in osteoclast cAMP levels

• In kidney, CT increases urinary excretion of calcium and phosphate

Causes of hypercalcemia

• Rarely seen under normal circumstances

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• Individuals with a low calcium diet, suddenly ingesting a large amount of calcium-rich food

Causes of hypocalcemia

• Daily losses in urine

• Fasting

• Diets deficient in calcium

 Regulation of intracellular calcium

• Calmodulin (CaM)

- 148 aa protein

- Ubiquitous distribution in eukaryotes

- 4 calcium-binding sites

- Binding of 3 or 4 calcium activates CaM

 Three major roles of calmodulin

• Regulation of intracellular calcium

- Increases activity of Ca2+-ATPase on the membrane of organelles if cytosolic calcium is excessive

• Enzyme activation

- Direct or indirect

- CaM can stimulate both ACase and PDE with different efficiencies

• Control of filamentous organelles (actin-myosin)

- Muscle contraction

- Chromosome movement

 Pathophysiology

• Hypocalcemia- neuromuscular excitability, tetany, cardiovascular dysfunction, GI malabsorption

- Hypoparathyroidism

 Physical or surgical trauma to parathyroids

 Autoimmune destruction of parathyroids

 DiGeorge syndrome (absence of parathyroids)

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- Pseudohypoparathyroidism

 Target organs are resistant to PTH action

 Pathophysiology

1) Hypercalcemia- neuromuscular suppression, bone pain, osteoporosis, kidney stones cognitive

impairment

 Hyperparathyroidism

• Adenoma or hyperplasia (defective calcium sensor) of parathyroids

• Vitamin D deficiency

• Chronic kidney disease