Regulation of Calcium Flashcards
Macrominerals (major minerals)
> 5g of mineral found in body and over 100 mg/day is needed (ex: calcium, chloride, magnesium, phosphorus, potassium, sodium, etc.)
Trace Minerals
Human body has <5g of mineral and less than 100 mg/day is needed
Calcium
- Most abundant mineral in body
- 99% in bones and teeth; 1% dissolved in blood (for muscle contraction, nerve transmission, allows secretion of hormones, digestive enzymes, NTs, activates cellular enzymes, blood clotting, cone constituent)
- Has to be ingested
- Normal blood calcium: 9-10.5 mg/dL
What are the three forms of calcium in the blood?
- Free-ionized-diffusible, biologically active
- Bound to anions (ex: phosphate): diffusible, not biologically active
- Proteins (albumin): not diffusible, not biologically active
What are the three main tissues involved in calcium regulation?
- Intestines: absorb more calcium
- Bones: release more calcium
- Kidneys: excrete less calcium
Calcium absorption
- Facilitated diffusion from entire small intestine
- Carrier mediated active transport under influence of vitamin D in duodenum
What are the three hormones involved in calcium regulation?
- Parathyroid hormone (PTH): increases blood calcium
- Vitamin D3: increases blood calcium
- Calcitonin: reduces blood calcium
What stimulates PTH secretion?
- Low blood calcium levels (hypocalcemia) = stimulates
- High blood calcium levels (hypercalcemia) = inhibit PTH release via negative feedback
- Calcium sensing receptors (CaSR) on parathyroid cells detect changes in calcium concentration
Explain the mechanism and signal transduction of PTH signaling.
- Mechanism: GPCR (PTH receptor type 1: PTH1R) -> activation of adenylate cyclase and increased cyclic AMP (cAMP)
- Signal transduction: PTH binds to PTH1R on target cells -> activates intracellular signaling pathways (cAMP and phospholipase C) -> physiological responses -> increase blood calcium levels
Explain the PTH action on bones.
- PTH stimulates osteoclast activity -> release of calcium and phosphate from bone into bloodstream
- Bone resorption releases calcium into bloodstream
- Bone formation stores calcium in bones
- Inhibits osteoblast activity
- Reduces bone formation in favor of increasing blood calcium levles
- Stimulates osteoclast activity indirectly via osteoblast signaling -> enhances bone resorption -> releasing calcium to raise blood calcium levels
- Stimulates osteoblasts to produce RANKL (receptor activator of nuclear factor k B ligand) -> binds to RANK receptors on osteoclast precursors -> promotes osteoclast formation and activation
Explain the PTH action on kidneys.
- PTH promotes calcium reabsorption in renal tubules
- Increases phosphate excretion (phosphaturia)
- Stimulates conversion of 25-hydroxyvitamin D to its active form, calcitriol (1,25-dihydroxyvitamin D3), which aids calcium absorption in gut
- Binds to receptors on principal cells of DCT
- PTH increases expression of TRPV5 channels -> allows more calcium to enter the renal tubular cells -> calcium transported out of cell via Na+/Ca2+ exchanger (NCX) in bloodstream
- PTH stimulates conversion of 15-hydroxyvitamin D to active form, calcitriol
Explain PTH action on intestine.
- Indirect action
- Indirectly increases calcium absorption in intestine through its stimulation of calcitriol production in kidney
Osteoblasts
- Cells responsible for bone formation
- Produce the bone matrix and promote mineralization (calcium deposition in bone)
Osteoclasts
- Cells responsible for bone resorption (breaking down bone tissue)
- Dissolve bone matrix and release stored calcium into bloodstream
What regulates PTH secretion?
- Calcium levels: low calcium -> PTH release (high calcium -> inhibits PTH release)
- Negative feedback: rising calcium levels suppress PTH secretion via feedback to parathyroid gland
- Activated vitamin D (calcitriol) suppresses PTH production by inhibiting PTH gene transcription
Vitamin D
- Fat soluble vitamin
- Requires bile for absorption
- Stored in liver and fatty tissues until needed
- Not needed in daily diet
- Can reach toxic levels if too much consumed
- Deficiencies can occur when people eat diets that are extraordinarily low in fat
- Can be self-synthesized by liver with the help of sunlight or obtained from food
- Vitamin D precursor is made from cholesterol
Calcitriol
- Active form of vitamin D (also known as 1,25- dihydroxyvitamin D3)
- Synthesized in the kidneys from 25-hydroxyvitamin D by enzyme 1alpha-hydroxylase (under influence of PTH)
- Steroid hormone that binds to the vitamin D receptor (VDR) on target cells (nuclear receptor) -> enters nucleus and activates the transcription of genes responsible for calcium and phosphate transport (Increases expression of calcium-binding proteins)
- Negative feedback loop: increased calcium levels= reduced PTH and 1alpha-hydroxylase activity -> limited calcitriol production
Explain the effects of calcitriol signaling.
- Increases calcium absorption: increases expression of calcium-binding proteins in the small intestine -> enhanced calcium absorption from food
- Calcitriol increases calcium reabsorption in renal tubules -> reducing loss of calcium through urine - Stimulates bone mineralization: promote the deposition of calcium and phosphate into the bone matrix, aiding in bone formation and strength
- High levels of calcitriol and calcium inhibit further production of calcitriol, maintaining homeostasis
Rickets
- Vitamin D or calcium deficiency in children
- Bones fail to calcify normally, growth retardation
- Symptoms: bone pain or tenderness, dental deformities, decreased muscle strength, skeletal deformities (abnormally shaped skull, bowlegs, and rib-cage abnormalities
Calcitonin
- Peptide hormone produced by the parafollicular (C) cells of the thyroid gland
- Primary role: regulates blood calcium levels, acting as an antagonist to PTH
- Released in response to high blood calcium levels (hypercalcemia)
- Binds to calcitonin receptor (CTR) on osteoclasts: GPCR (activates adenylate cyclase, increases cAMP)
- Negative feedback loop: calcium levels drop = calcitonin release is inhibited
Explain the effect of calcitonin on bones.
- Binds to calcitonin receptor on basal osteoclast surface (GPCR activation -> adenylate cyclase activation -> ATP converted to 3’,5’-cAMP -> increases cAMP levels)
- Decreased number of arms formed in the ruffled border (site of enzyme secretion and bone resorption)
- Decrease bone resorption
Explain the effect of calcitonin on calcium excretion.
- Calcitonin increases calcium excretion in urine
- Binds to calcitonin receptor (CTR) on cells of kidney (particularly in the distal convoluted tubule (DCT) and collecting duct)
- cAMP pathway activation -> PKA activation -> series phosphorylation
- Calcitonin reduced activity or expression of TRPV5 -> less calcium being taken up from the tubular fluid
- Calcitonin indirectly affects calcium absorption in intestines (regulation of vitamin D metabolism): inhibits activation of vitamin D by suppressing enzyme 1alpha-hydroxylase in kidneys (responsible for converting inactive vitamin D into calcitriol)
- Decreased calcitriol levels = decreased calcium absorption in intestine
Parathyroid Hormone (PTH)
- Produced by parathyroid glands in response to low calcium levels
- Binds to PTH receptors (PTH1R) on target cells (receptors located in bone (osteoblasts -> osteoclasts) and kidneys
- Negative feedback loop: increased calcium levels inhibit further PTH release
Explain the signaling pathway of PTH.
- PTH binds to PTH1R on target cells
- Activates GPCR pathway
- cAMP production and activation of protein kinase A (PKA)
- Stimulates bone resorption, increases kidney calcium reabsorption, and activates vitamin D
Explain the calcitonin signaling pathway.
- CTR: calcitonin receptor on osteoclasts
- GPCRs
- REduce osteoclast activity through cAMP and PKA pathways
- Inhibits bone resorption and promotes calcium excretion in kidneys
What happens with hypocalcemia (low calcium)?
- PTH released -> stimulates calcium release from bones, increases kidney reabsorption, activates vitamin D
- Calcitriol increases calcium absorption from intestines
- Negative feedback: rising calcium inhibits PTH release and vitamin D production
What happens with hypercalcemia (high calcium)?
- Calcitonin released -> inhibits bone resorption, promotes calcium excretion
- Negative feedback: failing calcium inhibits calcitonin release