Calcium Homeostasis

16.4.1 Introduction

Nearly 99% of the total calcium is present in bones and teeth, with 1% inside cells and 0.1% in circulation. The ionized calcium (Ca²+) present in circulation plays an indispensable role in blood coagulation, excitation of neurons, and contrac­tion of smooth muscle/cardiac cells/skeletal muscles.

Fig. 16.19 Biological effects of catecholamines. [Catecholamines increase the heart rate, blood flow to skeletal muscles, and catabolism of glucose and fatty acids to support the increased skeletal muscular activity to either fight or avert a threat in animals. [" increase; # decrease]

Table 16.4 Hormones involved in calcium (Ca2+) homeostasis

16.4.2 Parathormone(PTH)

PTH is a single-chain polypeptide hormone isolated initially in the bovine parathyroid gland.

16.4.2.1 MechanismofAction

PTH binds to at least three specific types of GPCRs known as parathormone receptors 1/2/3 (PTH 1/2/3R). When bound to PTH, they trigger the production of second messengers such as cAMP and calcium to activate PKA and PKC, respec­tively. PTH activates PTH1R present on osteoblasts and tubular epithelial cells making them major target cells.

16.4.2.2 Biological Effects

The target effects of PTH on kidney and bone are aimed principally at increasing circulatory Ca²⁺ levels (hypercalce­mia). Further, PTH facilitates the activation of Vitamin D₃ (Vit.D) in kidneys, thereby indirectly stimulating the intesti­nal absorption of dietary Ca²⁺.

16.4.2.2.1 EffectonBone

PTH acts on osteoblasts and stimulates the release of bone degrading proteases and cytokines that activate osteoclasts.

Fig. 16.20 Regulation of calcium by PTH [Parathormone increases the resorption of Ca²+ from the bones and kidneys to restore the circulatory Ca²⁺ levels to normalcy. CaSR calcium- sensing receptors; Ca²⁺ calcium ion; P_i inorganic phosphorus; RANKL receptor activator of nuclear factor kappa B ligand; M-CSF macrophage colony­stimulating factor; MCP-1 monocyte chemoattractant protein-1; " increase]

Two such molecules that mediate activation and differentia­tion of osteoclasts are the macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor kappa B ligand (RANKL).

16.4.2.2.2 EffectonKidney

PTH stimulates the tubular reabsorption of Ca²⁺ by upregulating the Ca²⁺-ATPase and Na⁺-Ca²⁺ antiporter genes in ascending loop of Henle and distal convoluted tubule (DCT). It also inhibits the reabsorption of P_i in the proximal tubule, thus useful in excreting excess P_i (phosphaturic effect) accumulated during bone resorption. In addition, it stimulates the production of calcitriol (1, 25-dihydroxy cholecalciferol) by upregulating the 1- α-Hydroxylase gene in the kidney and increases the absorp­tion of Ca²⁺ from GIT. Overall, increased mobilization of Ca²⁺ from bone with concurrent inhibition of its excretion produces the hypercalcemic effects of PTH (Fig. 16.20).

16.4.2.3 Regulation of Secretion

The calcium-sensing receptors (CaSR) present on chief cells will help to detect the minute-to-minute variations in circula­tory Ca²+ levels. Increased binding of Ca²+ to CaSR results in the inhibition of PTH release from the chief cells, whereas vice versa is true for PTH release. Since the parathyroid is bestowed with an exceptional sensitivity toward circulatory concentration of Ca²⁺, it is the foremost regulator of Ca²⁺ homeostasis.

16.4.3 Calcitriol (1, 25-Dihydorxy Cholecalciferol)

Vit.D₃ (Cholecalciferol) is a secosteroid derived from the precursor 7-dehydrocholesterol in the skin or from dietary supplements.

25-hydroxycholecalciferol (25-hydroxy Vit.D₃). Finally, 25-hydroxycholecalciferol (Calcidiol) is further hydroxylated by 1α-hydroxylase in proximal tubular cells to produce the active form of Vit.D₃, i.e.,

1, 25-dihydroxycholecalciferol, also known as calcitriol. The upregulation of 1α-hydroxylase is independently stimulated by a fall in Ca²⁺ and increased PTH in the blood (Fig. 16.21).

16.4.3.1 MechanismofAction

Calcitriol binds to vitamin D receptor (VDR) localized in the nucleus, fundamentally a type of ligand-dependent transcrip­tional factor. Expressed in various tissues, VDR is abundant in bones, intestinal epithelium, parathyroid gland, skin, and even in germ tissues. Once activated, VDR forms a hetero

Fig. 16.21 Biosynthesis and mechanism of action of calcitriol [The cholecalciferol produced in the skin is sequentially hydroxylated in liver and kidneys to yield the active form calcitriol. The calcitriol produced binds to the VDR present in the nucleus to produce the target effects. [PTH parathormone; VD calcitriol; VDR Vit.D receptor; RXR retinoid X receptor; " Increase]

dimer with RXR and binds to a specific DNA region known as vitamin D response element (VDRE). The binding of heterodimer results in the transcriptional activation of differ­ent genes that contribute to producing the biological effects.

16.4.3.2 Biological Effects

Calcitriol acts in concert with PTH to elevate the blood Ca²+ levels back to normal. Its major targets tissues are bones and the intestine epithelium. Apart from the hypercalcemic effect, calcitriol also regulates cellular proliferation, differentiation, and immune response.

16.4.3.2.1 Effects on the Intestinal Epithelium

Calcitriol stimulates enterocytes to produce more calcium- binding protein (CaBP), Na⁺-Ca²⁺ pumps and increases the brush border permeability to Ca²⁺. The Ca²⁺ forms a complex with CaBP and is subsequently absorbed into the blood. The presence of a Na⁺-Ca²⁺ pump on the basolateral membrane helps in pumping out the Ca²⁺ accumulated in the enterocytes to the blood. The Na⁺-K⁺ ATPase pump is very much essen­tial to maintain the activity of the Na⁺-Ca²⁺ pump and hence this method of Ca²⁺absorption is energy-dependent and con­sidered an active process. Additionally, the Ca²⁺-CaBP com­plex can be translocated from the gap junctions between the enterocytes or by fusing with lysosomes and exocytosed into the blood. Furthermore, it also increases the intestinal absorp­tion of phosphate, thus increasing its concentration in blood.

16.4.3.2.2 EffectsontheBone

Calcitriol has a synergistic effect on the PTH-mediated resorption of Ca²⁺ from the bone. It activates osteoclasts by stimulating the paracrine signals from osteoclasts. In the absence of calcitriol, the effect of PTH on osteoclast activa­tion is negligible.

16.4.3.3 Regulation of Secretion

The activation of Vit.D₃ depends on the circulatory levels of PTH and Ca²⁺. Elevated PTH in the blood increases the calcitriol formation, whereas increased levels of Ca²⁺ result in the conversion of 25-hydroxycholecalciferol to inactive 24, 25-dihydroxy cholecalciferol.

16.4.4 Calcitonin

Calcitonin is a polypeptide hormone secreted from C-cells (also known as parafollicular cells) in the thyroid gland. The mature hormone consisting of 32 amino acids is derived from the precursor prohormone molecule with 136 amino acids.

16.4.4.1 Mechanism of Action

Calcitonin binds to calcitonin receptors (CTR) that belong to the GPCR superfamily. The activation of CTR initiates both AC and PLC systems to initiate downstream signaling pathways in the target cells, especially in renal tubular epi­thelial cells and osteoclasts.

16.4.4.2 Biological Effects

Released in response to hypercalcemia, calcitonin acts to bring the circulatory Ca²⁺Ievels back to normal. It acts on the osteoclasts to suppress their release of acid phosphatase, motility, and differentiation resulting in the inhibition of bone resorption. In addition, calcitonin inhibits the renal tubular reabsorption of Ca²⁺ promoting its excretion. Together, a concurrent decrease in Ca²⁺ release from bone and its simul­taneous excretion from kidneys produce a hypercalcemic effect.

16.4.4.3 Regulation of Secretion

Secretion of calcitonin is chiefly triggered by the rise of Ca²⁺ concentration in blood.

Know More...

Hyperparathyroidism: A pathological condition characterized by increased secretion of PTH.

Hypoparathyroidism: Condition characterized by decreased secretion of PTH.

Milk fever: A metabolic disease in post-parturient cows due to the decreased calcium levels in blood.

Rickets: Deficiency of Vit.D3 resulting in the abnormal bending of bones in young animals.

Osteomalacia: Deficiency of Vit.D3 in adult animals leading to an abnormal softening of bones.

Renal rickets: A pathological condition characterized by the absence of 1α-hydroxylase in kidneys and subsequent deficiency of calcitriol.

Learning Outcomes

• Thyroid hormones: Thyrocytes present in the thy­roid follicles synthesize triiodothyronine (T₃) and tetraiodothyronine (T₄) from the amino acid tyro­sine. While T₄ is the major secretory form (90%), biological effects are due to T₃. Hence, T₄ is converted to T3 in the target cells by the action of deiodinases. It stimulates glycogenolysis, gluconeo­genesis, and glycolysis in the liver resulting in the increased secretion of glucose into the circulation. T₃ stimulates glucose uptake, glycolysis, and pro­tein degradation in skeletal muscle to generate more nutrients. Moreover, increased nutrients along with an increased mitochondrial number and activity to augment oxidative phosphorylation and subsequent thermogenesis.

• Glucagon: It is a polypeptide hormone released from the α-cells in response to hypoglycemia. Glucagon stimulates the rate of production of glu­cose from the liver by stimulating glycogenolysis, gluconeogenesis, and β-oxidation of fatty acids with concomitant inhibition of glycolysis. It also produces a marked degradation of skeletal muscle protein and lipolysis in adipose tissue to produce glucose via gluconeogenesis. The resultant increase in blood glucose levels supports the functioning of brain and other glucose-dependent cells present in the body.

• Insulin: Insulin produced from the β-cells is the only hypoglycemic hormone produced in animals. It is a heterodimeric polypeptide hormone released during hyperglycemia. It stimulates the glucose uptake in skeletal muscles and adipocytes to pro­duce glycogen and triglycerides, respectively. It inhibits glucose production by inhibiting gluconeo­genesis and stimulates protein synthesis in both the liver and skeletal muscles. The anabolic effects thus produced by insulin make it as one of the crucial mediator of growth due to GH.

• Mineralocorticoids: Mineralocorticoids are implicated in regulating the electrolyte balance and circulatory fluid volume. Aldosterone is the major mineralocorticoid synthesized exclusively in zona glomerulosa due to the presence of aldosterone synthase. Hyperkalemia is the most potent stimula­tor for aldosterone secretion, followed by angiotensin-II. Primarily, it affects principal cells and intercalated cells in distal tubules to increase Na⁺ reabsorption, K⁺ excretion, H⁺ secretion, and water reabsorption. These biological effects result in bringing down the K⁺ ion levels and restoring circu­latory volume.

• Glucocorticoids: Released from zona fasciculata, they are responsible for regulating glucose levels in circulation. Cortisol is the major glucocorticoid present in most animals, whereas corticosterone is the primary glucocorticoid in birds, mice, and rats. The glucocorticoids have a catabolic effect on gly­cogen, protein, and adipose tissue stores present in an animal’s body. Thus, the activation of various catabolic pathways results in hyperglycemia to sup­port the functioning of glucose-dependent vital organs such as the brain during stress. In addition to its effects on metabolism, it causes potent inhibi­tion of immune responses.

• Ca²⁺ homeostasis: Parathormone, calcitriol, and calcitonin constitute the triad of hormones that regulates calcium homeostasis. Parathormone and calcitriol are released from the parathyroid gland and kidneys, respectively, to elevate blood Ca²⁺ levels. During the period of hypocalcemia, they stimulate the reabsorption of Ca²⁺ from bone and kidney, increase the intestinal absorption of Ca²⁺ and renal excretion of phosphorus (P_i). Calcitonin released from the thyroid gland during hypercalce­mia increases the renal excretion of Ca²⁺, thereby decreasing the Ca²⁺levels back to normal.

(continued)

Exercises

Objective Questions

Q1. The glycoprotein secreted by the thyrocytes is known as

Q2. The iodide trapping seen in the thyroid gland is an example of type of active transport

Q3. ______________ is the enzyme required for the con­

version of iodide into iodine in the thyroid gland

Q4. What is the major form of thyroid hormone produced by the thyroid gland?

Q5. What is the major plasma protein to which the thyroid hormones bind in the circulation?

Q6. The group of enzymes that metabolism of the thyroid hormones in the target tissue are known as

Q7. The increase in the metabolic heat production by the thyroid hormones in the target tissues is an example for the_______________ type of thermogenesis

Q8. What is the major endocrine cell type present in the islets of Langerhans?

Q9. What is the pancreatic hormone released during hypoglycemia?

Q10. The insulin receptor belongs to the _______________

family

Q11. _____________ is the widest layer in adrenal cortex

Q12. The embryological origin of the adrenal medulla is

Q13. The adrenal catecholamines are derived from amino acid

Q14. What is the major mineralocorticoid secreted from the adrenal cortex?

Q15. The major type of corticosteroid in birds and reptiles is

Q16. Which hormone is responsible for the aldosterone escape?

Q17. Which catecholamine preferentially binds to the β type of adrenergic receptors?

Q18. The hypercalcemic hormone is produced by cells present in the parathyroid gland

Q19. The last step in the activation of calcidiol to form calcitriol is catalyzed by the enzyme

Q20. The parafollicular cells in the thyroid gland are respon­sible for the production of hormone

Subjective Questions

Q1. Describe the process of iodide trapping in thyroid follicles.

Q2. Explain the sequential steps in thyroid hormone synthesis

Q3. How the thyroid hormones are transported in blood?

Q4. Describe the mechanism of action of thyroid hormones.

Q5. What are the biological effects of T₃?

Q6. Explain the regulation of the secretion of thyroid hormones.

Q7. What are the different cell types present in islets of Langerhans? Explain their endocrine function?

Q8. Describe the effects of glucagon on intermediary metabolism.

Q9. Describe the molecular mechanisms involved in the secretion of insulin

Q10. Briefly explain the intracellular signaling of insulin in target tissues.

Q11. Substantiate why insulin is known as an anabolic hormone.

Q12. Explain the histology of the adrenal gland.

Q13. Write a short note on the synthesis of mineralocorticoids

Q14. Describe the biological effects of aldosterone.

Q15. List out different glucocorticoids and their biosynthesis.

Q16. Why the secretion of glucocorticoids is considered essential for life?

Q17. What is the hypothalamus-pituitary-adrenal (HPA) axis?

Q18. Explain the steps involved in the synthesis of adrenal catecholamines.

Q19. Explain the events in the fight or flight response.

Q20. Explain the hormonal regulation of Ca²⁺ homeostasis

Answer to the Objective Questions

A1. Thyroglobulin

A2. Secondary

A3. Thyroid peroxidase (TPO)

A4. T₄(Thyroxine)

A5. Thyroxine-binding globulin (TBG)

A6. Deiodinases

A7. Non-shivering thermogenesis

A8. β-cells

A9. Glucagon

A10. Tyrosine kinase

A11. Zona fasciculata

A12. Neural ectoderm

A13. Tyrosine

A14. Aldosterone

A15. Corticosterone

A16. Atrial natriuretic peptide (ANP)

A17. Norepinephrine

A18. Chief cells

A19. 1α-hydroxylase

A20. Parathormone

Keywords for the Answer to Subjective Questions

A1. Sodium (Na⁺)-Iodide (I^-) symporter (NIS), secondary active transport, pendrin

A2. Iodine uptake, organification^ endocytosis

A3. Thyroxine-binding globulin (TBG), thyroxine-binding prealbumin (TBPA or Transthyretin), serum albumin

A4. MCT 8, 5'-deiodinase type 1 (D1), 5'-deiodinase type 2 (D2), thyroid receptors (TRs), retinoid X receptor (RXR), thyroid response element (TRE)

A5. Increases glucose production, basal metabolic rate (BMR), glycolysis, gluconeogenesis, glycogenolysis, lipolysis, basal metabolic rate (BMR).

A6. Hypothalamic-Pituitary-Thyroid axis, TRH, and TSH

A7. α cells-glucagon, β cells-Insulin, δ cells-somatostatin, and F∕γ cells-pancreatic polypeptide

A8. Inhibition of glycolysis and glycogenesis, catabolism of lipids and amino acids, hyperglycemia, ureagenesis

A9. GLUT2, K_atp channels, Ca²⁺ channels, and exocytosis A10. Insulin receptor (IR), tyrosine kinase, insulin receptor substrate 1-6 (IRS 1-6), PI3K∕AKT pathway, Raf∕Ras∕ MEK/MAPK pathway

A11. Decreased glycogenolysis, increase in glycogenesis, inhibit gluconeogenesis, protein synthesis in the liver, decrease lipolysis, increase lipogenesis

A12. Zona glomerulosa, zona fasciculata, zona reticularis, and adrenal medulla

A13. Pregnenolone, progesterone, 11-deoxycorticosterone, corticosterone, aldosterone synthase, aldosterone

A14. Principal cells (PC), epithelial sodium channels (ENaC) genes, Na⁺-K⁺ ATPase, intercalated cells (IC), H⁺ ATPase, H⁺ ion secretion, normovolemia

A15. Cholesterol, pregnenolone, 11-deoxycorticosterone, corticosterone, cortisol

A16. Gluconeogenesis, glycogenolysis, lipolysis, hyperglycemia

A17. Hypothalamus-CRH, anterior pituitary gland-ACTH, adrenal-cortisol

A18. Phenylalanine, tyrosine, dihydroxy-phenylalanine (DOPA), dopamine, norepinephrine, epinephrine

A19. Increased cardia output, blood flow to skeletal muscle, increased muscular activity, and glycogenolysis

A20. Parathormone, calcitriol, and calcitonin

Further Reading

Textbooks

Feingold KR, Anawalt B, Boyce A, et al (eds) (2000) Endotext. South Dartmouth, MA: MDText.com, Inc. https://www.ncbi.nlm.nih.gov/ books∕NBK278943∕

Hall JE, Hall ME (2020) Guyton and Hall textbook of medical physiol­ogy e-Book. Elsevier Health Sciences

McDonald LE, Pineda MH, Dooley MP (2003) McDonald’s veterinary endocrinology and reproduction. 5th ed./edited by M.H. Pineda, with the editorial assistance of Michael P. Dooley. Ames, Iowa: Iowa State Press. Print

Nussey SS, Whitehead SA (2001) Endocrinology: an integrated approach. https://www.ncbi.nlm.nih.gov/books/NBK22

Reece WO, Erickson HH, Goff JP, Uemura EE (eds) (2015) Dukes’ physiology of domestic animals. Wiley

Takei Y, Ando H, Tsutsui K (eds) (2015) Handbook of hormones: comparative endocrinology for basic and clinical research. Aca­demic Press. https://doi.org/10.1016/C2013-0-15395-0

Articles

Braun D, Schweizer U (2018) Thyroid hormone transport and transporters. Vitam Horm 106:19-44. https://doi.org/10.1016/bs. vh.2017.04.005

Citterio CE, Targovnik HM, Arvan P (2019) The role of thyroglobulin in thyroid hormonogenesis. Nat Rev. Endocrinol 15(6):323-338. https://doi.org/10.1038/s41574-019-0184-8

Feldt-Rasmussen U, Rasmussen AK (2007) Thyroid hormone transport and actions. Pediatr Adolesc Med 11(R):80

Fleet JC (2017) The role of vitamin D in the endocrinology controlling calcium homeostasis. Mol Cell Endocrinol 453:36-45. https://doi. org∕10.1016∕j.mce.2017.04.008

Goltzman D (2018) Physiology of parathyroid hormone. Endocrinol Metab Clin 47(4):743-758. https://doi.org/10.1016Jj.ecl.2018. 07.003

Janah L, Kjeldsen S, Galsgaard KO, Winther-S0rensen M, Stojanovska E, Pedersen J, Wewer Albrechtsen NJ (2019) Glucagon receptor signaling and glucagon resistance. Int J Mol Sci 20(13):3314. https://doi.org/10.3390/ijms20133314

Kim K, Kopylov M, Bobe D, Kelley K, Eng ET, Arvan P, Clarke OB (2021) The structure of natively iodinated bovine thyroglobulin. Acta Crystallogr D Struct Biol 77(11):1451-1459. https://doi.org/ 10.1107∕S2059798321010056

Mullur R, Liu YY, Brent GA (2014) Thyroid hormone regulation of metabolism. Physiol Rev 94(2):355-382. https://doi.org/10.1152/ physrev.00030.2013

Newton R (2000) Molecular mechanisms of glucocorticoid action: what is important? Thorax 55(7):603-613. https://doi.org/10.1136/thorax. 55.7.603

Vegiopoulos A, Herzig S (2007) Glucocorticoids, metabolism and met­abolic diseases. Mol Cell Endocrinol 275(1-2):43-61. https://doi. org∕10.1016∕j.mce.2007.05.015

Veerappa S, McClure J (2020) Intermediary metabolism. Anaesth Inten­sive Care Med 21(3):162-167. https://doi.org/10.1016Zj.mpaic. 2020.01.003

William Tank A, Lee Wong D (2011) Peripheral and central effects of circulating catecholamines. Compr Physiol 5(1):1-15. https://doi. org/10.1002/cphy.c140007