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Medsci 312 > Lecture 28; Hormonal Regulation of Ca homeostasis > Flashcards

Lecture 28; Hormonal Regulation of Ca homeostasis Flashcards

1
Q

What are the values of Ca in circulation + IC and intersitial?

A
  • Circulating concentrations - maintained in narrow range -2.25-2.55 mmol/L
  • Low intracellular calcium concentration - 0.1 to 1μM
  • Intermediate interstitial compartment calcium - 1.5mM
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2
Q

Where is the Ca in the body?

A

• Major constituent of ALL cell types

• Approximately 1.2kg of calcium in the adult human
body and most is stored as bone
• Approximately 350mg is in plasma and about half of this is unbound and biologically active
• Approximately half of the calcium in plasma is bound to plasma proteins, mainly albumin, while 10% is complexed with citrate

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3
Q

What is the function of 99% of Ca?

A

Calcified matrix of bone

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4
Q

What is the role of Ca in the ECF?

A

0.1%

  • Cement for tight junctions
  • Role in myocardial and SM contraction
  • Role of neurotransmitter release
  • Neuron excitability
  • Cofactor in coagulation cascade
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5
Q

What is the role of Ca in the ICF?

A

0.9%

Secondary messenger pathways

Muscle contraction

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6
Q

What does Ca play a critical role in?

A
  • Bone mineralization
  • Blood clotting
  • Muscle contraction
  • Enzymatic action
  • Release of hormones and neurotransmitters • Nerve function
  • Cell division and proliferation
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7
Q

Why must Ca be balanced???

A
  • There is a continuous exchange of calcium between different calcium pools in the body
  • A balance between the various pools must be maintained because calcium is critical to so many physiological functions
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8
Q

Describe age and Ca balance;

A
  • Childhood - calcium balance is positive (new bone laid down)
  • Young adulthood - daily uptake (from gut) = daily losses (urine and sweat)
  • Older age - calcium balance is negative (greater output) (losing bone)
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9
Q

Where does Ca come from?

A
  • Recommended around 1g dietary calcium per day (abundant in cheese and milk)
  • Around 30% of ingested calcium is absorbed - highly regulated and decreases with age
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10
Q

What hormones control Ca movement?

A
  • Three hormones control calcium balance to regulate movement between gut, bone and kidney
  • Vitamin D or calcitriol acts to increase calcium
  • Parathyroid hormone (PTH) acts to increase calcium
  • Calcitonin acts to decrease calcium (C cells in thyroid gland)
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11
Q

Describe the movement of Ca from digestion;

A

Ca is absorbed from the gut into the ECF (this is controlled by calcitriol (Vit-D) and PTH) (2.5mM range)

Passive filtration in the kidney, some Ca lost in urine. (PTH increases absorption, Calcitonin decreases it)

or

from ECF Ca can be taken up into the bone (calcitonin does this)

However PTH, Vit-D causes the release of Ca from bone.

or

Active Transport of Ca into the cells

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12
Q

Where does PTH come from?

A

• Produced from the parathyroid gland (4 glands); Chief cells secrete PTH

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13
Q

What stimulates PTH release and what does it do?

A
  • A decrease in plasma calcium (unbound) (ENDOCRINE REFLEX) stimulates release of PTH
  • PTH stimulates an increase in plasma calcium by acting on intestine (absorb), bone (Release) and kidney (Absorb)
  • Increased plasma calcium shuts off PTH secretion (classical negative feedback pathway)
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14
Q

Describe the pathway for PTH release;

A

CaR (GPCR) sits in plasma membrane of chief cell and senses Ca

Gsα to increase cAMP and Gqα to stimulate phospholipase C (PLC)

Ca binding causes PLC activation

  • DAG -> PKC = inhibits PTH synthesis
  • IP3 -> Ca store release = Inhibits PTH release

Lack of Ca binding

  • cAMP increases
  • Increases PTH syntheses (transcribe and translate)
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15
Q

How large is PTH and what allows it to be biologically active?

A

PTH is synthesized as a large precursor protein and then cleaved to a 84 amino acid peptide prior to storage in vesicles in the chief cells

The first 34 amino acids is sufficient for full biological activity

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16
Q

Where are PTH receptors found?

A

PTH receptors expressed in renal tubule cells (reabsoprtion), bone osteoblasts (Ca release) and gut epithelial cells (absoprtion)

17
Q

Describe how PTH causes renal reabsoprtion of Ca?

A

Directly acts on receptor to cause an increase of reabsoprtion in Ca and increase PO4 secretion

This also causes the kindeys 1a hydroxylase activity to increase producing active form Vit-D which increases Ca absorption from the gut

18
Q

How does PTH cause increased Ca release from the bone?

A

Acts on osteoblasts which release Osteoclast Activating Factors.

This increases their activity and Ca release.

19
Q

What is Vit D?

A
  • The term Vitamin D is used when it is not necessary to distinguish between vitamin D2 and vitamin D3
  • Vitamin D is classified as a vitamin but since only 10% is acquired in the diet in the form of vitamin D2, it would be better classified as a hormone
  • Vitamin D is derived from cholesterol and has structure similar to steroid hormones
  • Dietary vitamin D2 - fish and eggs
  • Vitamin D3 accounts for 90% of total vitamin D and is synthesized in the skin under the influence of ultraviolet light
20
Q

Where does Vit D3 become activated?

A
  • Vitamin D is activated by undergoing two enzymatic additions of hydroxyl groups
  • Liver - inactive vitamin D is converted to 25-hydroxyl vitamin D
  • Kidney - 25-hydroxyl vitamin D is converted to the active 1,25 dihydroxyvitamin D also known as calcitriol
21
Q

How does activated Vit-D work?

A

Diffuses into a cell like steroid hormone. Binds to receptors and regulates transcription.

22
Q

How is calcitriol inactivated?

A
  • Inactivated in the kidney by 24-hydroxylase to 1,24,25 tri-hydroxy vitamin D
  • Activity of 24-hydroxylase is increased by high calcium concentrations
23
Q

What are the concentrations of active and inactive calcitriol?

A
  • Concentration of inactive 25-hydroxycholecalciferol in plasma is high - 3-30 μg/L
  • Concentration of active calcitriol is low - 20 -60 ng/L
  • Production of active vitamin D is tightly regulated and subject to feedback control
24
Q

Describe the regulation of calcitriol;

A
  • The enzyme, 1α-hydroxylase converts 25-hydroxy vitamin D to 1,25-dihydroxy vitamin D in the kidney
  • Low calcium or phosphate stimulates 1α-hydroxylase activity (ENDOCRINE REFLEX)
  • Synthesis of 1α-hydroxylase is increased by PTH, growth hormone, cortisol, oestrogens and prolactin (Regulating factors)
  • High calcium activates 24-hydroxylase leading to increased inactive 1,24,25 trihydroxy vitamin D (Negative feedback)

Ca homeostasis!

25
Q

What are the mechanisms of action for calcitriol?

A
  • Similar to steroid hormones, vitamin D diffuses through the cell membrane and and binds to specific receptors in the nucleus
  • Promotes synthesis of proteins involved in calcium absorption
26
Q

What are the actions of vit-d?

A
  • Gut - vitamin D increases absorption of dietary calcium and phosphate by unknown mechanism
  • Bone - vitamin D increases release of calcium and phosphate by activating osteoclast activity
  • Kidney - vitamin D increases calcium and phosphate reabsorption
  • Inhibits PTH release

• Outside calcium metabolism, vitamin D effects insulin sensitivity and cell differentiation

27
Q

What is release in response to high Ca?

A

Calcitonin from C cells in thyroid gland

28
Q

Write some brief notes on calcitonin;

A

• Secreted from the C cells of the thyroid gland in response to a rise in calcium levels
• Acts to reduce calcium levels (opposes PTH)
• Calcitonin plays a minor role in DAILY calcium
balance in adult humans

29
Q

Where does Calcitonin act?

A
  • Acts by binding to specific G-protein coupled receptors present in renal tubule and osteoclasts
  • Kidney: calcitonin inhibits calcium and phosphate reabsorption
  • Bone - calcitonin suppresses release of calcium and phosphate
30
Q

What stimulates calcitonin release?

A
  • High Ca
  • Adrenalin, glucocorticoids, CGRP
  • Gastrin

= increase calcitonin

Somatostatin, calcitriol decrease calcitonin release

Medsci 312 (28 decks)

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