Calcium

why doesn’t the RDA for calcium increase for pregnant or breastfeeding woman

these women need more calcium for the body, but at the same time, the body becomes MUCH BETTER at absorbing/saving calcium during pregnancy

• intestines absorb more efficiently

• kidneys hold onto more calcium, less it lost in urine

• extra calcium is stored in bones

why is the UL reduced after age 50

with old people, their kidney’s do not work as efficiently

• slower filtration means they can’t get rid of excess calcium well

most menopausal women take calcium supplements to help prevent osteoporosis (bone loss). why can this be an issue

• some supplements contain a LOT of calcium

• women above 50 will take more than the UL

• too much calcium is also not good = can cause kidney stones and health issues

what are the best sources of calcium

1. dairy

2. plant-based foods adn vegetables

3. seafood

T/F Meat and grains are excellent sources of calcium

F

dairy, vegetables, and seafood are better

T/F calcium from food always enters the body unbound and free

F

calcium is a charged ion, it is almost ALWAYS bound. never' ‘free’ cause it would just immediately bind to something.

Calcium from food/supplements come in the form of ______________

insoluble salts

what dissolves calcium

stomach acid

explain the process of active transport for calcium absorption in the intestine

1. Calcium (Ca2+) enters intestinal cells from the lumen through TRPV6 

• TRPV6 → A calcium-selective ion channel that allows Ca to enter cells passively using the concentration gradient 

• Lumen → inside space of intestine where food is located

2. Inside the cell, D9K (calbindin) binds to Ca

• D9K → A calcium-binding protein shuttle that quickly moves calcium to the other side of cell for export 

3. Ca2+ is actively pumped out of the cell into blood by Ca2+/ATPase pumps on the basolateral membrane 

• Ca2+/ATPase → Protein that uses ATP to transport calcium against its concentration gradient into the blood

what is calbindin

another name for D9K

what do claudins have that help them hold enterocyte cells together in tight junction

cysteine bridges

what does it mean when we say the paracellular passive absorption of calcium in the intestine is NON-SATURABLE

transport does not have a max limit

• any amount of calcium in the lumen is going to get absorbed

• absorption increases with concentration

T/F Two foods that contain the same amount of calcium is going to be absorbed equally by the body

F

define chelation

a metal binding to a molecule to form a complex, which can affect bioavailability either positive or negative

calcium + oxalic acid forms what

calcium oxalate

what is phytate and where is it found

→ Natural compound found in plants such as unleavened bread, raw beans, seeds, nuts, and grains

• contains negatively charged phosphate groups, that bind to positively charged ions, forming an insoluble complex

how does yeast make calcium-phytate complex more bioavailable

yeast is a bacteria that produces phytase, an enzyme that breaks down phytate to free calcium

fatty acids and calcium forms _______

fatty soaps

list 2 features of fatty soaps

1. poorly soluble

2. precipitate out of solution (turns solid)

trophic effect meaning

something that helps another tissue grow, survive, or function

explain how fibre enhancers paracellular calcium absorption

1. fibre gets broken down in large intestine by bacteria, producing short-chain fatty acids

2. SCFA lower stomach pH, releasing more free calcium

3. this allows more calcium to be absorbed paracellularly through colon cells

colonocytes use SCFA’s for energy (trophic effect)

• SCFA’s promote growth and health of colonocytes, increasing absorptive surface

• larger surface = more calcium absorbed paracellularly

vegans have more SCFAs and colonic bacteria, explain how this increase calcium absorption

SCFA

• since vegans eat more fibre, when fibre is broken down, it releases a lot of SCFA

• SCFA lower the pH in colon to increase calcium absorption

• SCFA promote growth and health of colonocytes, increasing absorptive surface, allowing more calcium to be absorbed paracellularly through colonocytes

colonic bacteria

• fiber also feeds the bacteria in the large intestine

• bacteria secrete phytase, which releases free calcium bound to phytate.

• both benefit: bacteria gets food and humans get absorbable calcium

explain the 2 functions of SCFAs

1. lowers stomach pH, releasing more HCl to free calcium

2. food for colonocytes, increasing their absorptive surface for better paracellular calcium absorption

list 2 places PTH receptors are most commonly found

1. bone (osteoblasts)

2. kidney

this makes sense bc PTH acts DIRECTLY ON bone and kidney to raise blood Ca levels.

explain how PTH directly increases calcium absorption on bone

1. PTH binds to PTH receptor located on osteoblasts

2. This induces transcription of the RANKL gene

3. RNAKL binds to RANK protein receptor located on pre-osteoclasts

4. Osteoclast differentiation occurs 

5. Osteoclasts can now do its job, start bone resorption, and release calcium into the blood.

T/F The only transporter that brings calcium into cells in the kidney is TRPV5

T- ish

TRPV5 is the major kidney calcium channel, while TRPV6 is the major INTESTINE calcium channel. But TRPV6 is also present in the kidneys, just at a lower amount

what is the primary regulator of calcium absorption in the intestine

Vitamin D!!

it induces transcription of all the proteins/channels involved (TRPV6, D9K, Claudins 2 and 12)

what is the primary regulator of calcium absorption in the kidneys

PTH!!

it induces transcription of TRPV5, D28K

Vitamin D can also help with D28K, but PTH can raise D28K on its own

T/F are PTH and Vitamin D able to induce transcription of D28K together to increase bone resorption of calcium?

Yes, together is stronger. they are also able to both do it independently without each others help

is phosphorylation genomic or non-genomic

non-genomic bc you don’t need to change the DNA

list 2 ways PTH directly helps the kidneys reabsorb calcium so it doesnt get lost in urine. how does it indirectly help?

1. induces transcription of D28K

2. increase TRPV5 activity through phosphorylation (non-genomic)

• can do this as well as induce transcription of TRPV5

indirectly

• triggers 1-alpha-hydroxylase synthesis in the kidneys

• this makes more active Vit D, which goes to intestines to absorb more calcium

Vitamin D works best aka increases calcium absorption most efficiently where:

1. intestine

2. kidney

3. bone

intestine

• the main site where vitamin D maximizes calcium absorption

define calcitonin and what it does

→ a hormone secreted by parafollicular cells in the thyroid gland to reduce blood calcium levels

• inhibits osteoclast activity to reduce bone resorption

• impairs osteoclast differentiation to reduce formation of mature, active osteoclasts

name of cells that secrete calcitonin

parafollicular cells in the thyroid gland

name of hormone whose main job is to lower blood calcium

calcitonin

list the 2 main hormones for increasing blood calcium

1. PTH

2. VItamin D (calcitriol)

when does PTH act non-genomically to increase calcium absorption

to increase activity of the TRPV5 transporters in renal tubule cells for kidney reabsorption.

• does so through phosphorylation

summarize quickly how PTH and Vitamin D regulate (increase) calcium absorption, including both genomic and non-genomic pathways

PTH

genomic

• induce transcription of D28K in renal tubule cells (directly)

• induce transcription of 1-alpha-hydroxylase in kidneys (indirectly)

• induce transcription of RANKL to increase bone resorption (directly)

non-genomic

• increase activity of TRPV5 through phosphorylation

VITAMIN D

genomic

• induce transcription of TRPV6, D9K, Ca2+-ATPase, Claudin 2 and 12 for intestinal absorption

• induce transcription of TRPV5, TRPV6, D28K, and Ca2+-ATPase for kidney reabsorption

• induce transcription of RANKL for bone resorption

  • leads to differentiation of pre-osteoclasts → mature osteoclasts, to release HCl and hydrolytic enzymes that break down hydroxyapatite and the organic matrix (osteoid collagen) to return calcium into blood

non-genomic

• acts as a ligand to activate MARSS, which activates G protein, leads to a cascade of signals that leads to PKA phosphorylating VDCC, opening up calcium channels.

T/F Vitamin D can upregulate transcription of PTH

F

it can downregulate but not upregulate

what happens when CaSR is inhibited or activated?

when activated (by high extracellular blood calcium), CaSR suppressed PTH

when inhibited and inactive, it allows for normal PTH secretion

vitamin d has a lot of functions where it induces transcription of genes, name one example where it negatively regulates a genes and decreases its transcription

explain the process of 24-hydroxylase synthesis. is it genomic or non-genomic

its genomic

1. Vit D calcitriol binds to nVDR —> RXR —> induces transcription of 24-hydroxylase gene on the VDRE (vitamin d response element)

2. 24-hydroxylase turns both existing calcidiol and calcitriol into 24,25(OH)2 Vit D (inactive)

3. it competes with 1-alpha-hydroxylase for the substrate, calcidiol.

list all the genes located on the Vitamin D response element

1. 24-hydroxylase

2. CYP27B1

3. CYP2R1

4. RANKL

5. TRPV6

6. Calbindin D9K and D28K

7. Gene for Ca2+-ATPase

which organ synthesizes 24-hydroxylase

primarily the kidney

but intestine, bone, and parathyroid gland can also express 24-hydroyxlase to inactive Vit D locally

both Vitamin D and PTH can induce transcription of RANKL, which one primarily does it

PTH

• has a stronger signal for RANKL and bone resorption

• Calcitriol can also contribute but its main role is increasing intestinal calcium absorption

How to turn off Vitamin D once blood calcium homeostasis is restored

list the 5 main functions of calcium

1. neurotransmitter release

2. skeletal muscle contraction

3. smooth muscle contraction

4. signal transduction

5. blood clotting

6. bone mineralization

explain the general steps of a neurotransmitter release

1. signal is transmitted and sent to the neuron

2. depolarization occurs where the cell becomes less negative

3. this change in charge opens up VOLTAGE-GATED SODIUM CHANNELS, allowing Na to flow into cell, while K leaves cell

4. as the signal reaches axon terminal (end of neuron), this causes VOLTAGE GATED CA2+ channels to open

5. This causes vesicles to fuse with cell membrane, releasing neurotransmitters across the synapse

Calcium has a _________(higher/lower) concentration outside the cell, compared to inside

higher

• important for its functions

what happens after neurotransmitters are released into the synapse

it triggers depolarization of the next neuron

what would you expect would happen if there was LOW extracellular calcium? what actually happens ?

neurons will fire more

• you would expect neurons to fire less since there’s less calcium outside the cell = less calcium enters the cell = less neurotransmitters fire

1. extracellular calcium regulates the voltage-gated Na channels that open when depolarization occurs within a neuron

• on its own, Na channels can’t fully close and will leak a bit Na into the cell, even at rest

2. Calcium can bind to the Na channels, to either block or slow down Na leaking in

3. Without enough extracellular calcium, there isn’t enough to regulate Na leakage

4. This can cause a lot of Na to leak in, causing the neuron to depolarize spontaneously

5. this fires a lot more neurons, and releasing neurotransmitters even when there isn’t enough extracellular calcium

define depolarization

when a membrane potential becomes less negative (more positive)

what are the 2 channels involved in neurotransmitter release

1. Voltage gated sodium channels

2. Voltage-dependent Ca2+ channels

what causes a muscle contraction to occur

1. myosin pulls on the thin filaments of actin, shortening the muscle

2. this is what causes a muscle contraction to occur

calcium is the signal that triggers muscle ___________

contraction

explain the process of smooth muscle contraction and how calcium is involved

• calmodulin

• MLCK

1. calcium rises in the cell, binding to calmodulin

2. calcium-calmodulin complex activates MLCK

3. MLCK phosphorylates the light chains on myosin

4. now myosin can bind onto actin = smooth muscle contraction

define troponin

protein complex on actin thin filaments of skeletal muscle, that sense calcium and begin contracting

• once calcium binds to troponin C, it pulls away from the binding site, exposing it for myosin to attach onto = muscle contracts

summarize the main difference between smooth and skeletal muscle contraction

skeletal: binding site on actin is unbound by calcium, allowing myosin to bind

smooth: myosin must be activated by calcium, calmodulin, then phosphorylated by MLCK in order to bind onto actin.

define signal transduction

how a cell takes a signal (hormone, neurotransmitter or ligand) and turns it into a response inside a cell

• signal → receptor → response

• a ligand (signal molecule) binds to a receptor on a cell, triggering a series of events that lead to a cellular response

T/F signal transduction always involves calcium binding to calmodulin

F

usually yes, but calcium can also WORK/ACT alone by binding directly to enzymes

what is the main calcium sensor in signal transduction

calmodulin

what is the name for calcium when its involved in blood clottin g

Factor IV (5)

when talking about signal transduction in the formation of blood clots, does calcium work alone or together with calmodulin

calcium (factor IV) works alone

• it activates enzymes, phospholipase C and A, which help make prostaglandins → signals inflammation, pain, adn recruits repair cells

define prostaglandins

involved in blood clotting.

• they are made by the enzymes phospholipase C and A

• it signals inflammation, pain, and recruits immune & repair cells

what does it mean when we say calcium acts like a bridge in blood clotting

calcium helps clotting proteins bind onto negatively charged surfaces, like the membrane

• remember calcium is positively charged this helps form a FIBROUS PATCH for the cut/wound, to stop bleeding

is most of bone made up of the inorganic or organic matrix

inorganic (hydroxyapatite mineral)

• makes up 2/3 of bone

define bone mineralization

depositing hydroxyapatite crystals (calcium and phosphate) into the organic matrix

list and describe the two types of inorganic bone mineral

1. non/poorly crystalline minerals

• found on the surface of bones

• easily dissolves if blood calcium drops → helps to maintain calcium levels

• responds to Vit D and PTH, activating osteoclasts

• eg. tricalcium phosphate and brushite

2. crystalline minerals

• found deeper in bone

• turns over slowly, much harder to dissolve

• releases calcium VERY SLOWLY into the body

• eg. hydroxyapatite is the major form

____________(surface/deep) inorganic crystalline minerals → first to release calcium for blood.

____________(surface/deep) inorganic crystalline minerals → provide long-term strength for bone 

surface;deep

what are the causes of rickets

1. mainly vitamin D deficiency

2. calcium deficiency

3. both

what are rickets

disease specifically in children where bones become weak and soft

T/F Rickets can occur in people of all ages

F

only children

T/F Breastmilk contains a lot of Vitamin D

F

thats why rickets occur

explain why breastmilk is always a good source of calcium