Calcium and Phosphorus Flashcards
What are relevant dietary characteristics of Calcium?
- Has 2 valence electrons which are lost readily in solution creating Ca2+ which is the preferred dietary state
- Ca2+ has tight configuration (low radius) on its own but can attract H2O to form large ‘effective ionic radius’.
- Limited Ca2+ intracellular movement due to membrane permeability so it is useful for other interactions within cell
- Binding constant of Ca2+ can change, interacts with array of different molecules
Biological functions of Ca2+
- Bone mineralization
- Considered an intermediate messenger carrier so can initiate series of processes
- Rapid rise and fall of Ca2+ with cell activation allows functions to be performed
Calcium role in bone mineralization
A part of hydroxyapetite (along with P) which is component of bone & teeth which most calcium is here
* 99% of calcium is mineralised in bone
Where is the rest of Ca2+ outside of bone storage?
Of the remaining 1%, ~half is as ionized to the active form Ca2+ (active form) such that increases in intracellular calcium may act on cell directly or via calcium binding proteins to regulate processes such as:
* blood clotting
* nerve conduction
* muscle contraction
* enzyme regulation
* membrane permeability
How does Ca2+ iniate extracellular processes
low intracellular concentration of <0.01% maintained by pump but can enter cytoplasm extracellularly or intracellularly through cell activation (depolarization, NT, hormones & second messengers) and the rapid rise and fall allow functions
What are specific examples of Ca2+ role extracellulary?
- Platelet PLA2: hydrolyzes AA from PL in cell membranes to form prostaglandins, thrombboxanes, leukotrienes
- Protein kinase C: Stimulates PKC which phosphorylates enzymes that stimulate/inhibit metabolic pathways
- Calmodulin: binds 4 Ca2+ & changes conformation/ability to interact with calmodulin-dependent enzymes such as calcineurin & phosphorylase kinase
What pathways can Ca2+ follow to get into the cell to exert its actions on a cell?
- voltage dependant slow channel (extra- to intra-)
- agonist dependant channel (extra- to intra-)
- diffusion (depends on cell permeability) (extra- to intra-)
- Inositol triphosphate (IP3) messenger pathway (fron intra-)
How does Ca2+ exit the cell into circulation?
- ATP-dependant pumps using Mg2+ and Na+
- ATPase
Describe the voltage dependant slow channel for Ca2+ entering the cell
Indirect influx of Calcium from extracellular space by changing intracellular
electrical properties of membrane
* Signals from outside of cell influence the channels conformation allowing influx of non specific ions
Describe the agonist dependant channels for Ca2+ entering the cell
Calcium specific channel activated through ligand binding so Ca2+ enters from extracellular space and it can then act directly or as second messenger.
* muscle contraction (direct)
* secretion (direct)
* calmodulin (second messenger)
Describe the IP3 messenger pathway for Ca2+ release
- G coupled protein activates phospholipase C
- PIP2 hydrolyzed whereby the IP3 is soluble and diffuses into cell and DAG stays in membrane but both are second messengers
- IP3 binds to Ca2+ channel in ER whereby Ca2+ can come into cytosol and cause a response or act as a second messenger
- DAG is used in signal transduction and lipid signalling
Role of Ca2+ as a second messenger in the cell
4 Ca2+ from intracellular or extracellular release can bind to calmodulin which changes its conformation/ability to interact with calmodulin-dependent enzymes such as calcineurin & phosphorylase kinase to induce a response such as contraction, metabolism or transport
Chemical characterisitics of Phosphorus
- Majority of phosphorus stores in the body are found in bone as hydroxyapatite (80-90%)
- Preferred ionic state in solution is orthophosphate
- P likes to bind certain moelcules with high energy binding capacity so acts as buffering system to pick up excess ions
Biological function of Phosphate
- Bone mineralization
- Electrolyte homeostasis, acid-base balance
- Structural role
- energy storage and transfer (ATP)
- Second messenger
- Metabolic trapping reactions
- physiological buffer
How does phosphate act as a physiological buffer?
Has 2 main forms at pH 7.4 and is used by the body to prevent large changes in the pH of bodily fluid by taking H+ in the tubular fluid
Phosphate role in DNA structure
Phosphate alternates with pentose sugars to form linear backbone of nucleic acids DNA and RNA
* important for the helix
Phosphate role in ATP and energy release
Role in energy storage and transfer (includes nucleotides & derivatives)
* Molecules form high energy phosphate bonds used in intermediary metabolism such as those in ATP, creatine phosphate, UTP and GTP… Also NADP
Role of phosphate as a second messenger
- P is part of cyclic adenosine monophosphate (cAMP) which is derived from ATP in response to hormone-receptor binding and activates protein kinases
- Many enzyme activities are controlled by phosphorylation and dephosphorylation
- P is part of Inositol triphosphate (IP3) which acts to trigger intracellular Ca2+ release as mediated by protein kinases
Describe Calcium absorption
Be able to draw
Typically only 20-30% effective
* major route is transcellular mostly in duodenum: saturable form that requires energy + channel + calbindin binding protein; it is stimulated by low Ca diets & calcitriol (genomic mechanism).
* Paracellular route mostly in the ileum/ jejunum: non-saturable form which is passive and concentration dependent
* 4-10% may be absorbed through colonic fermentation of fibres that release Ca2+
Describe phosphorus absorption
Be able to draw!
60-70% effective
* Absorbed linearly to intake, preference as HPO42-, mechanism similar to Ca2+ but little is known about the details
* Twice as efficient as Ca2+ absorption, responds to calcitriol but less so than Ca2
What are the 2 main hormones associated with Calcium and phosporus and where do they come from?
- calcitonin from thyroid gland (ventral)
- parathyroid hormone from parathyroid glands (dorsal)
When are PTH and calcitonin released?
- PTH: low Ca2+
- caltitonin: high Ca2+
How is PTH release controlled?
By plasma Ca2+ feedback mechanism
* controls PTH production and secretion
Where does PTH come from?
parathyroid hormone which is a peptide hormone produced by the parathyroid gland
Where does PTH act?
cell surface receptors often indirectly vis second messenger system adenylate cyclase, cAMP, protein kinase primarily for:
* bone
* kidney
Role of PTH in bone
Acts (indirectly) on the osteoblasts to stimulate release of Ca from the skeletal pool to increase circulation Ca
* may also stimulate increased absporption but mostly from bone
Role of PTH on kidney
- Acts (indirectly) on kidney tubular cells which respond to PDH by ↑ Ca re-absorption but simultaneously ↓ re-absorption of phosphate so more phosphate is excreted.
- PTH regulates conversion of vitmain D to active form in the kidney
Describe and draw the process for blood calcium regulation when Ca2+ is low
- ↓ blood Ca signals parathyroid gland to release PTH into blood
- PTH binds to bone cell receptors and triggers the resorption or breakdown of bone mineral for the release of Ca into the blood
- PTH acts on the kidneys to synthesis the active form of vitamin D, caltitriol
- PTH and calcitriol promote the reabsorption of Ca from the kidney and into the blood
- Calcitriol leaves the kidney and goes to the intestine to stimulate absorption of Ca
- Ca enters the bloods after release from bone and kidneys and absorption from intestive.
Where does calcitonin come from?
peptide hormone that is secreted from the thyroid gland
What is the role of calcitonin?
Opposite effects of PTH, Calcitonin increases bone mineralization and deposition of Ca+2 (storage) and reduces Ca+2 absorption from the kidneys.
Draw the regulation of Calcium and phosphate
impact of PTH and calcitriol on:
* Vitamin D
* kidney
* bone
* Ca2+ release
* intestine
* blood Ca2+
How much skeletal bone is replaced each year in adults?
~10% of skeletal bone mass replaced every year in adults (complete structural overhaul every decade) due to constant remodelling
Why is bone replacement important?
- Allows bone to support the body/allow movement
- incubate developing immune cells
- act as a reserve of inorganic minerals
- Remodelling repairs bone defects and helps maintain optimal levels of calcium in the blood
What are the 2 main bone cells and their roles?
- Osteoclasts destroy and resorb old bone
- osteoblasts deposit new bone in its place
Processes are coupled
What the general cycle of bone remodelling?
- Activation phase (~40 days) - involves conversion of osteoclast precursor cells to active osteoclasts
- Reversal phase (~145 days) - allows transition from bone resorption to formation
What stimulates and inhibits osteoclasts?
- stimulates - pro-resorptive and calciotropic factors
- inhibits - anti-resorptive or anabolic factors activate osterblasts to lay down new bone
Draw calcium and phosphorous homeostasis
What are good sources of calcium?
- milk or yogurt; nonfat, plain
- cheddar cheese
- fortified tofu
- fortified OJ
- fortified soy milk
Adequate vs. averahe calcium intake over the life cycle
Average intake is well below what is reccomended
Ca DRIs
% Ca absorbed compared to total Ca absorbed/ serving for some common foods
- the % absorbed may be high, but product itself might not have much Ca
P RDIs
- AIs for Infants is based on mean intakes of breast-fed infants
- RDAs are based on EAR + 20%
- In children: estimated using body accretion corrected for absorption efficiency, urinary losses - must retain P for bone growth
- Criteria for adequacy in adults = serum concentration
- Pregnancy and Lactation - No evidence for increased requirements
Food sources of P
Widely distributed
* Protein sources (meat, milk, eggs, cereals) usually high in P
* Diary products, meat, fish, poultry & eggs supply ~70% of typical intakes
* Processed foods & soda contain P as additives
Causes of hypocalcemia
- hypothyroidism
- inadequate vitamin D production
- vitamin D resistance
- PTH resistance
Clinical consequences of hypocalcemia
- asymptomatic, fatigue
- neuromuscular irritability
- bronchospasm
- Altered CNS function
- cardiomyopathy
Causes of hypercalcemia
- hyperabsorption of Ca
- Decreased urinary excretion due to defect
- increased bone resorption
- severe dehydration
- idiopathic hypercalcemia
clinical consequences of hypercalcemia
What happens with the bone remodelling cycle in osteoporosis?
bone formation and resorption not as closely coupled such that resorption occurs more which can make the bone brittle and fragile is susceptible regions
Describe type I osteoporosis
earlier onset in wrist in spine
Describe type II osteoporosis
onset with later age in the hip
Risk factors and protective factors for osteoporosis
bone loss compared over time with adequate Ca vs. inadequate Ca
Having enough Ca into adulthood sets up for better adaptation
Causes of hypophosphatemia
- vitamin D deficiency or resistance
- Increased urinary loss
- intracellular shifts
Clinical consequences of hypophosphatemia
- CNS problems
- decreased oxygen affinity
- muscle myopathy
- bone resorption
- electrolyte imbalance
- metabolic abnormalities
Causes of hyperphosphatemia
- decreased urinary excretion
- acute phosphate load
- altered extracellular space
- pseudohyperphosphatemia
Clinical consequences of hyperphosphatemia
