Calcium and Phosphorus Flashcards
What are the chemical characteristics of calcium?
- 2 valence electrons; lost readily in solution creating Ca2+
- Ca2+ (preferred state), tight configuration (low ionic radius), attracts H2O and has unique properties of a large ‘effective ionic radius’
- Binding constant of Ca2+ can change, interacts with array of different molecules
- Limited intracellular movement
Does Calcium have good intracellular movement? Why or why not?
Limited intracellular movement due to the permeability of the membrane
Why is Ca2+ ‘useful’? What about when it is free in the cell?
- Useful due to interaction with other ions and proteins within the cell (voltage gated channels specific for Ca2+)
- When calcium becomes freely available it is used as a signalling mechanism. It can then bind to other things as a second messenger
What are the major biological functions of calcium?
- Generally Ca2+ is considered a tool or carrier (intermediate messenger); does not necessarily cause the function but can initiate series of processes
- Bone mineralization
- Involved in pathways. Entrance can change muscle contractions, secretion, enzyme regulation, blood clotting, nerve conduction, and membrane permeability
What is the concentration of free calcium in the cell?
- Intracellular concentration of free Ca2+ (cytoplasm) is very low (<0.01% of extracellular fluid) - maintained by pumps
How does calcium enter cytoplasm extracellularly or intracellularly? What does this change in concentration do?
- Cell activation by depolarization, neurotransmitters, hormones, and second messengers results in calcium entering cytoplasm extracellularly or intracellularly
- Rapid rise and fall in cytoplasmic Ca2+ allows function to be performed
Why is calcium important for bone mineralization?
- Component of bone and teeth as hydroxyapetite - contains both calcium and phosphorous
- 99% of calcium (and 80-90% of phosphorous) in bone
- Biggest storage of calcium is in the skeleton. If you don’t keep calcium in balance you start to draw on skeletal stores. Big problem when you are older - osteoporosis
If most of calcium is stored in the bone, where is the remaining? What does this effect?
- Of the remaining 1%, ~half is as ionized Ca2+ (active form)
- Increases in intracellular calcium (cytosolic) may act on cell directly or via calcium binding proteins to reglate processes such as blood clotting, nerve conduction. muscle contraction, enzyme regulation, membrane permeability
Give 3 specific examples of how calcium in active form can impact proteins
- Platelet PLA2 - hydrolyzes AA from PL in cell membranes to form prostaglandins, thrommoxanes, leukotrienes
- Protein kinase C - phosphorylates enzymes that stimulate/inhibit metabolic pathways
- Calmodulin - binds 4 Ca2+ and changes conformation/ability to interact with calmodulin-dependent enzymes such as calcineurin and phosphorylase kinase
How does calcium impact electrical properties of the cell?
- Indirect influx of calcium can change intracellular electrical propertes of the membrane/cell
- Calcium concentrations can cause conformational changes of ligand-gated channels. Ions move inside through oopen channel changing electrical properties of cell
Explain how cytosolic calcium levels through ligan-gated channels can impact the cell
- Specific calcium channels exist that allow entry of calcium upon binding of a messenger
- Once calcium enters through the open channel muscle contraction, secretion, and binding of second messengers (calmodulin) occurs
- Upon binding to calmodulin, complex can activate enzymes such as protein kinase which activates proteins and leads to responses in cell such as muscle contraction, altered metabolism, and altered transport)
How does intracellular calcium impact calmodulin?
- Calcium influx and the release of calcium stores by IP3 binds to inactive calmodulin (4 Ca2+ to one calmodulin)
- Active calmodulin binds to calmodulin-dependent enzyme and then activates the enzyme
- This leads to a
How does intracellular calcium impact calmodulin?
- Calcium influx and the release of calcium stores by IP3 binds to inactive calmodulin (4 Ca2+ to one calmodulin)
- Active calmodulin binds to calmodulin-dependent enzyme and then activates the enzyme
- This leads to a change in cellular function
What are the effects of inositol triphosphate and DAG on calcium?
- Inositol triphosphate = IP3 which is a messenger pathway causing calcium release
- PI is phosphorylated to form PIP, PIP2, and PIP3
- IP3 (made by hydrolysis of PIP2) and DAG are second messengers used in signal transduction and lipid signaling
- DAG stays in the membrane and can cause phosphorylation of protein Kinase C to cause a response in the cell
- IP3 is soluble and diffuses through cell. It is a messenger that binds to a channel and causes calcium release from the ER. The calcium then causes responses in cell OR binds to calmodulin which can activate protein kinase where it is phosphorylated and a response occurs
How are calcium concentrations intracellularly regulated?
- Calcium enters cells by diffusion or channels and exerts its actions (e.g. Ca voltage dependent slow channels, Ca agonist-dependent channels)
- Calcium can be released from the ER or mitochondria
- ## Calcium can be removed from the cytoplasm in two ways: ATP-dependent pumps use magnesium and sodium to export calcium out of the cell, and ATPase and other pumps can sequester calcium in organelles such as the ER or mitochondrian
What are the chemical characteristics of phosphorus?
Where is it stored and its unique properties?
- Majority of phosphorus stores in the body are found in bone as hydroxyapatite Ca10(OH)2(PO4)6 (6 phosphate molecules to 10 calcium)
- Unique property of phosphorus is that the preferred ionic state (in solution) is orthophosphate as HPO4 2- and H2PO4- which has high energy binging capacity
- HPO42- + H+ <-> H2PO4-. At pH 7.4 ratio is 4:1.
- Acts as a buffer and mops up excess protons/ions floating around
- Body is better at absorbing than calcium, larger biological window in kidney
What are the biological functions of phosphorus?
- Bone mineralization
- Electrolyte homeostasis, acid-base balance
- Structural role
- Energy storage and transfer (ATP)
- Second messenger
- Metabolic trapping reactions by phosphate esters e.g. Vit B metabolism
- Physiological buffer
What is the structural role of phosphorus?
- DNA/RNA structure based on phosphate ester monomer
- Phospholipids (phosphate head group) - for biological detergents
How does phosphorus act as a second messenger?
Phosphorylation of proteins (kinases) and dephosphorylation (phosphatase) essential to molecular regulation
Why do we worry about phosphorus less than calcium?
- we can absorb phosphorus and phosphate more easily than calcium
- Phosphorus has a larger biological window in kidney to reabsorb if needed compared to calcoum
- Easier to get in the diet than calcium
- As a result of these lifespan issues not as prevalent as compared to calcium
How does phosphate act as a buffer?
- Dependent on what state it is in, more hydrogen = more acidic, less hydrogen = more basic
- Two main forms are at a pH of 7.4
Why is the buffer function of phosphate so important?
- water and carbon dioxide in the cytosol forms carbonic acid which dissociates into bicarbonate ions and hydrogen ions
- Bicarbonate leaves cell with the help of Cl- whereas H diffuses out or uses potassium antiporter
- Once in the tubular fluid phosphorus functions to mop up
How does phosphate impact the DNA structure?
- Phosphate alternates with pentose sugars to form linear backbone of nucleic acids DNA and RNA. Backbone is critical to form helix
How is phosphate involved with ATP and energy release?
- Involved in energy storage and transfer (includes nucleotides and derivatives)
- Forms high energy phosphate bonds used in intermediary metabolism such as those in ATP, creatine phosphate, UTP, GTP, and also NADP
- AKA need a phosphate to form high energy bonds used in metabolism and for energy to do work (cellular movement, molecular synthesis, and transport across membranes)
How does phosphate impact intracellular second messengers?
- Part of cyclic adenosine monophosphate (cAMP), derived from ATP in response to hormone-receptor binding, activates protein kinases
- Many enzyme activities are controlled by phosphorylation and dephosphorylation
- Inositol triphosphate (IP3) acts to trigger intracellular Ca2+ release as mediated by protein kinases
How is calcium absorbed? Is it effective?
- Calcium absorption is typically only 20-30% effective
- Transcellular (major route) - saturable, requires energy + channel + binding protein (calbindin), stimulated by low Ca diets and calcitriol (genomic mechanism → mostly duodenum
- Paracellular - non-satuable, energy independent (passive), concentration dependent → mostly ileum/jejunum
- Colonic fermentation of fibres may relase Ca (4-10% of dietary calcium may be absorbed this way)
- Pathways can be upregulated with calcium rich diet or using hormones that act on intestine to maximize calcium absorption
How is phosphate absorbed? Is it effective?
- 60-70% effective
- Absorbed linearly to intake (As you consume more you absorb more), preference as HPO42-, mechanism similar to Ca2+ but little is known about the details
- Twice as efficient as calcium absorption, responds to calcitriol but less so than calcium
- Can get into enterocyte by diffusion or carrier-mediated active transport, gets into blood and complexes with other minerals
How is calcium absorbed transcellularly?
- Calcium binds to the protein calbindin for absorption into the intestinal cell via a channel and for transport across the cytosol in the basolateral membrane
- ATPases pup calcium across the basolateral membane into blood in exchange for magnesium and sodium
What can increase calcium absorption?
- increased 1,25(OH)2D
- Increased estrogen
- Increased PTH
What glands are responsible for calcium and phosphate metabolism and what do they impact?
- Thyroid gland (located in front) → calcitonin
- Parathyroid gland (located in back) → parathyroid hormone
Explain the 6 steps of calcium regulation
- Low blood calcium signals the parathyroid gland to release PTH into the blood
- PTH binds to bone cell receptors and triggers the resorption or breakdown of bone mineral for the release of calcium into the blood
- PTH acts on the kidneys to synthesize the active form of vit D, calcitriol
- PTH and calcitriol promote the reabsorption of calcium from the kidney and into the blood
- Calcitriol leaves the kidney and travels into the intestine where it promotes the synthesis of calbindin, which facilitates calcium absorption across the brush border membrane of intestinal cells and its transport in the cell cytoplasm
- Calciem enters the blood after release from bone, after release from kidneys, and absorption from intestinal cells
Explain how calcitonin and PTH interact
- When calcium is high in the blood, calcitonin levels will be high and PTH levels will be low. Calcitonin inhibits resorption of calcium from the bone
- When calcium is low, PTH is high and Calcitonin is low. Will cause increased reabsorption from bone, and kidney, and activation of Vit D. Calcium will then increase and phosphate levels will decrease. More phosphate will be excreted out and less calcium will be excreted
What will occur when calcium levels in blood are low?
What will occur when blood calcium levels are high?
Explain the bone remodelling cycle. What can this lead to?
- Because it takes a long time to form bone and increase mineralization, in abnormal conditions bone may not be able to catch up with degradation
- Osteoclasts cab resorb, whereas osteoblasts help with bone formation, and osteocytes help with mineralization
- Activation phase involves conversion of osteoclast precursor cells to active osteoclasts
- Reversal phase allows transition from bone resportion to formation
How much calcium and phosphorus is actually absorbed? Where do these amounts go?
- Dietary intake may have 700mg/d of phosphorus and 1000mg/d of calcium
- Only 20-30% of calcium is absorbed and 60-70% of phosphorus is absorbed. the rest is secreted
- Calcium absorption can be higher in growth, pregnancy, and lactation
- Majority of both calcium and phosphorus goes to skeleton, some extracellular fluid pool. Some that goes to kidney, some calcium going to skin
What impacts calcium bioavailabiity and what foods have the greatest amount of calcium absorbed?
- Bioavailaibility is affected by fibre, phytate, oxalate, and protein
- Milk or yogurt, cheddar cheese, and fortified tofu, OJ, and soy milk have the greatest amount of calcium absorbed despite having low % absorbed
- Foods like plant based foods and whole wheat bread have a greater % of calcium absorbed but because they have low amounts of calcium they have less total absorbed
Food sources of calcium equivalent to 1 milk serving
How do calcium intake and DRIs over the life cycle change?
- Seem to only reach our DRIs until age 9, afterwards lower amounts than recommended
What are the calcium DRIs over the life cycle?
What are the best food sources of calcium?
- Majority of calcium in NA diets is from milk and milk products
- Non-dairy sources include calcium-set tofu and some green vegetables
- Calcium fortified foods are now available
What are the RDAs/AIs of phosphorus over the life cycle?
What are the food sources of phosphorus?
- Widely distributed
- Protein sources (meat, milk, eggs, cereals) usually high in P
- Dairy products, meat, fish, poultry and eggs supply ~70% of typical intakes
- Processed foods and soda contain P as additives
What are the causes and clinical consequences of hypocalcemia?
What are the causes and clinical consequences of hypercalcemia?
Explain the following picture
Calcium deficiency over time may lead to osteoporosis. As a result, the back may lose length due to collapse of spinal bones. Collapsed vertebrae cannot protect the spinal nerves from pressure that causes excruciating pain
What happens to bone structure with osteoporosis?
- Erosion of trabecular bone can occur in osteoporosis
- Bone formation and resorption is not as closely coupled and more resorption is formed caused bone to become thinner, and weaker
What are the types of osteoporosis and how do they differ?
- Type 1 = postmenopausal osteoporosis
- Type 2 = senile osteoporosis
- Type 1 onset is early and impacts trabecular bone whereas Type 2 impacts trabecular and corticol bone
- The gender incidence is much higher for type 1 than type 2
- The primary cause of type 1 is from estrogen loss or testosterone loss in men whereas type 2 is from reduced calcium absorpion, increased bone mineral loss and likelihood of falling
List risk factors and protective factors for osteoporosis
How is bone lost over time?
- Reach peak bone mass by age 30
- Over time gradually lose bone mass but is accelerated after menopause
- To prevent going into danger zone need to have higher bone masses to begin with by having vitamin D and calcium early on
What are the main causes and clinical consequences of hypophosphatemia?
- caused by the intracellular shift of P from serum into cells, increased urinary excretion of phosphate, or decreased intestinal absorption
What are the causes and clinical consequences of hyperphosphatemia?
