Calcium Homeostasis - Part 1 PDF

Taken from https://www.newcastle-hospitals.nhs.uk/services/endocrine-and-thyroid-surgery/ BS31019 – Calcium homeostasis – Part 1 Dr Claire Y Hepburn  Learning outcomes Learning outcomes Describe the biological functions of Ca2+ Identify the hormones that regulate ex...

Taken from https://www.newcastle-hospitals.nhs.uk/services/endocrine-and-thyroid-surgery/ BS31019 – Calcium homeostasis – Part 1 Dr Claire Y Hepburn  Learning outcomes Learning outcomes Describe the biological functions of Ca2+ Identify the hormones that regulate extracellular Ca2+ levels, understand where these hormones are made and their mode of action. Describe the symptoms and signs of hypercalcaemia and hypocalcaemia. List the disorders that can cause these conditions. Describe the regulation of parathyroid hormone (PTH) synthesis and the role of Ca2+ sensing receptors. Describe how PTH exerts its effects on its target cells and list those effects. Describe the symptoms and signs of hyperparathyroidism and hypoparathyroidism. Describe how calcitonin exerts its effects on its targets cells and list those effects. Explain how vitamin D metabolism is regulated and describe how vitamin D exerts its effect on its target cells. Explain how PTHrP, FGF23, and gonadal and steroid hormones influence Ca2 +/Pi metabolism Presentation name, Your name, Date Recommended reading Medical Physiology. 3rd Edition. Elsevier. Chapter 52 – 1054-1069 Leach, K., et al., (2020). International Union of Basic and Clinical Pharmacology. CVIII. Calcium-Sensing Receptor Nomenclature, Pharmacology, and Function. Pharmacological Reviews, 72, 558-604. https://doi.org/10.1124/pr.119.018531 Khosla, S., and Munroe, D.G. (2017). Regulation of bone metabolism by sex steroids. Cold Spring Harbor Perspectives in Medicine, 8, https://doi.org/10.1101/cshperspect.a031211 BS12002 – Origins of animal organ systems – Connective tissue Physiological functions of calcium (Ca2+) Calcium (and phosphate) play significant role in formation of our skeleton and our teeth but they also play an important role in the regulation of biochemical pathways and signalling cascades Physiological functions of calcium Skeletal rigidity – hydroxyapatite and calcium phosphate Component of connective tissue and teeth Haemostasis (blood clotting) – intrinsic and extrinsic cascades Excitation-contraction coupling – smooth and striated muscle Stimulus-secretion coupling – acetylcholine from the neuromuscular junction Cell-to-cell adhesion - cadherins Second messenger for enzymatic activity - calmodulin  Whole body calcium handling 1 Ionised which means it is free and biologically active. 2 Protein bound and non-diffusible. Biologically inactive and not excreted. 3 Complexed with phosphate, bicarbonate or citrate. Whole body calcium handling [Dietary Ca2+] [Ca2+ resorbed from bones] = [Ca2+ lost in faeces, sweat and saliva] [Ca2+ deposited in bone] Physiological functions of inorganic phosphate (Pi) Physiological functions of inorganic phosphate Formation of bone – calcium phosphate and hypoxyapatite crystals Formation of ATP Component of nucleotides, nucleosides and phospholipids Aids in cellular signalling through it’s role phosphorylating proteins and as a constituent of second messengers Normal values Normally inorganic phosphate exists as HPO4- or H2PO4- Plasma concentration = 2.3 mmol l-1 Calcium homeostasis The homeostasis of plasma calcium is achieved by the actions of three different hormones that act on bone, kidneys and intestines. These hormones are: Metabolites of vitamin D (1, 25- Dihydroxyvitamin D) Parathyroid hormone (PTH) Calcitonin Adapted from Medical Physiology, 3rd Edition, 2017. Parathyroid hormone Manufactured in chief cells of the parathyroid glands and the most important of the three hormones – responds to hypocalcaemia. Stored as pre-pro or pro-hormone, cleavage of leader and pro-sequences yield a biologically active peptide of 84 amino acids Free calcium is ‘sensed’ by calcium sensing receptors (CaSR) expressed Heterozygous CaSR inactivating mutation in FHH means failure of inhibition of PTH secretion in high [Ca2+]e Heterozygous CaSR and Gα11 gain-of- function mutation in ADH means high 2+ urinary excretion of Ca in normal [Ca ]e 2+ Adapted from Medical Physiology, 3rd Edition, 2017. Calcium-sensing receptors (CaSR) GPCR which responds to numerous ligands Divalent and trivalent cations, peptides and polyamines Not all roles are related to calcium homeostasis CaSRs mediate numerous physiological effects Extracellular calcium homeostasis Nutrient sensor – parietal and G cells Enzyme secretion – α cells and β cells CaSR – Gq/11 – IP3 and DAG – IP3 increases [Ca2+]i and DAG activates PKC. Parathyroid hormone (PTH) PTH (aka PTH/PTHrP) receptors are expressed on osteoblasts in bone and in the proximal and distal tubules of the kidneys. Overall PTH is responsible for increasing extracellular Ca2+ Bones - 1° PTH stimulates cytokines that recruit osteoblasts Osteoblasts induce osteoclasts GI tract - 2° Activates synthesis of 1,25-dihydroxyvitamin D (kidney) and increases transcellular uptake of Ca2+ from the small intestine Kidneys - 1° PTH increase Ca2+ reabsorption by increasing activity of Ca2+ channels and pumps Thyroidectomy, which commonly removes the parathyroid gland also, would be fatal, except for the fact that there are small clusters of PTH producing cells, outside of the parathyroid gland, along the trachea. Metabolites of vitamin D…1, 25-Dihydroxyvitamin D Vitamin D (cholecalciferol) is a prohormone Converted to active 1, 25- dihydroxyvitamin D (calcitriol) by hydroxylations Second hydroxylation is regulated by Growth hormone = ↑ Prolactin = ↑ Oestrogen = ↑ FGF23 = ↓ 1, 25-Dihydroxyvitamin D = ↓ Adapted from Medical Physiology, 3rd Edition, 2017. Metabolites of vitamin D…1, 25-Dihydroxyvitamin D The primary role of 1,25-dihydroxyvitamin D is to contribute to homeostasis of calcium Small intestine Diffuses into enterocytes and binds to vitamin D receptor (VDR) and increases gene expression Increases calcium transport across the enterocyte membrane by increased expression of apical Ca2+ channels and basolateral Ca2+ transporters. Kidneys Increases expression of Na+-Pi cotransporter and improves PTH-mediated Ca2+ reabsorption Bone Increases number of osteoclasts Calcitonin Manufactured in clear cells of the thyroid glands and plays a role in responding to hypercalcaemia but function in healthy individuals is probably very limited (thyroidectomy) Synthesised from a pro-hormone to eventually produce a biologically active peptide of 32 amino acids Antagonistic action of PTH Bone Osteoclasts express calcitonin receptors and binding of calcitonin reduces the rate 2+ of bone turnover and therefore release of Ca in bone Adapted from Medical Physiology: Principles for Clinical Medicine, 5th edition, 2017 Other hormones involved in calcium homeostasis Other homeostatic events influence homeostasis of calcium Factors which influence bone turnover Sex hormones Oestrogen is responsible for maturation of bone into adulthood in both sexes Testosterone maintains bone density Glucocorticoid Regulate bone density and intestinal calcium absorption Parathyroid hormone-related protein (PTHrP) Mimics action of PTH in bones and kidneys but is produced outside the parathyroid glands. Can induce hypercalcaemia mostly by paracrine rather than endocrine signalling Inorganic phosphate metabolism Inorganic phosphate homeostasis Regulation of concentrations of inorganic phosphate = phosphatonins, PTH and calcitriol (1,25-hydroxyvitamin D) Most studied phosphatonin is fibroblast growth factor 23 (FGF23) FGF23 is secreted by osteocytes and its production is upregulated when plasma phosphate concentrations rise FGF23 stimulates phosphate loss in the urine PTH and calcitriol stimulate phosphate release from bone in combination with Adapted from Medical Physiology, 3rd Edition, 2017. release of calcium Hypocalcaemia Low plasma Ca2+ Total serum calcium < 0.5 mmol l-1 Ionised serum calcium < 0.3 mmol l-1 Symptoms and signs Pins and needles Muscle spasms (tetany) Paralysis Convulsions Hypercalcaemia High plasma Ca2+ Total serum calcium > 2.62 mmol l-1 Ionised serum calcium > 1.31 mmol l-1 Symptoms and signs Bones, stones, groans and psychiatric overtones. Lethargy Depression Constipation Renal calculi Frequent urination Nausea Arrhythmias Hypoparathyroidism Lack of PTH Due to lack of production or defects in the responsiveness of target tissues Symptoms and signs Muscle spasms - tetany Low plasma calcium - hypocalcaemia High inorganic phosphate - hyperphosphataemia Hyperparathyroidism Excess of PTH Primary Excess production of PTH from the parathyroid glands - tumours Secondary Chronic kidney disease i.e. lack of 1,25-dihydroxyvitamin D Calcium malabsorption i.e. gastric bypass surgery Symptoms and signs Hypertension Constipation Weakness Confusion High plasma calcium - Hypercalcaemia Too little vitamin D Summary Calcium exists in homeostatic flux between bound, as hydroxyapatite and calcium phosphate and to calcium-binding proteins, and unbound, ionised, free calcium. Homeostatic control is tightly regulated because of the numerous and key physiological roles calcium plays within our bodies The key regulators of calcium are: Metabolites of vitamin D (1, 25-Dihydroxyvitamin D) Parathyroid hormone (PTH) Calcitonin However, PTH, released from parathyroid cells is the primary means by which calcium concentrations are regulated (in response to hypocalcaemia) Other homeostatic events influence homeostasis of calcium, including sex hormones and glucocorticoids Thank you. Questions?