Lecture 17 Flashcards
(27 cards)
What are the calciotropic hormones? What does calciotropic hormones mean?
Calciotropic hormones are parathyroid hormone, calcitonin, and vitamin D.
Calciotropic hormones are the hormones that are going to be affecting calcium metabolism.
What are the role of calcium sensing receptors in the body?
Calcium sensing receptors in our body play a role in calcium homeostasis - they help our body known what the calcium levels are in your blood so that they can regulate their levels.
What are hormones?
Is it possible for calcium to be the fourth calcitropic hormone? Why?
Hormones are things that travel through the blood that binds to receptors to cause a response.
At high calcium levels calcium itself plays more of an important role than calcitonin (which doesn’t really do a lot) in lowering its plasma levels (meaning that calcium itself is a more effective hormone than calcitonin). The reabsorption of calcium in the kidneys is controlled (partially) by plasma calcium levels. This means that calcium has actual responses in these organs (binding to receptors and causing an effect).
Whats one example of the roles that growth factors and estrogen play with regards to calcium?
Growth factors and estrogen are very important in the calcium response throughout the body - for example, estrogen (and testosterone) play a big role in bones and bone development (men tend to have stronger bones than females; females develop osteoporosis as a result of a lack of estrogen).
What is vitamin D derived from, and what other molecule is derived from this same molecule? How is pro-vitamin D converted to vitamin D? What kind of molecule is this precursor of vitamin D, and what is its purpose?
Vitamin D is derived from cholesterol (through a multistep process), which is present in your skin. Cortisol is also derived from cholesterol as well.
Sunlight (in addition to heat) helps activate a specific enzyme to change pro-vitamin D (7-dehydrocholesterol, which is derived from cholesterol) into vitamin D.
Cholesterol is a steroid hormone which is important for plasma membrane fluidity and is a precursor to other steroid hormones (as well as bile acids).
Why is vitamin D actually not a vitamin? Why is there a catch to this?
Vitamin D is actually not a vitamin because vitamins are things (cofactors and coenzymes important for enzymatic function) that you need to obtain from your diet (because they are things that your body does not make on its own). Since vitamin D is made by the body (and matured through UV light), it is technically not a vitamin. However, if you don’t get enough vitamin D, you need to take a supplement
What form of vitamin D is present in your body after taking a supplement? What form is present in the kidneys? What form is present in the liver?
vit D3 —(liver)—> 25(OH) Vitamin D3 —(kidney)—> 1α,25(OH)2-Vitamin D3
What form of vitamin D binds to vitamin D receptors to cause biological responses? Where is this form of vitamin D made?
1α,25(OH)2-Vitamin D3 is made by the kidneys. The other form of vitamin D (24R,25(OH)2-D3) is not shown, but the hydroxy group is 1 carbon away from the green hydroxy group above.
Are vitamin D3 and 1α,25(OH)2-Vitamin D3 the same in terms of function (as well as structure and where they are derived from), or are they different?
No, vitamin D3 and 1α,25(OH)2-Vitamin D3 are not the same in terms of function or structure. 1α,25(OH)2-Vitamin D3 is the active steroid hormone form of vitamin D3. Vitamin D3 is biologically inactive itself, it does not bind to the vitamin D receptors, and this is the form that you get from your diet.
Your kidneys makes two different forms of vitamin D. What forms are made in the kidneys, and what are their purposes?
Your kidneys make 1α,25(OH)2-Vitamin D3, which binds to vitamin D receptors and plays a role in the vast majority of biological responses. Your kidneys also make 24R,25(OH)2-Vitamin D3, which also binds to vitamin D receptors - however it is going to be mostly involved in calcium homeostasis.
What stimulates vitamin D to become its active form (calcitriol) in the kidneys? What is calcitriol then responsible for making in the kidneys as well? Why?
Parathyroid hormone stimulates vitamin D to become its active form (calcitriol) in the kidneys. Calcitriol will then go on and help produce 24R,25(OH)2-Vitamin D3.
What does the active form of vitamin D (calcitriol) do when it circulates in the body?
When calcitriol is made (and then circulates in the blood) it is going to go to target tissues that have the vitamin D receptor (which is a nuclear receptor).
As soon as calcitriol (steroid hormone) enters cells with the vitamin D receptors, it binds to this receptor, thus allowing this activated receptor to be able to enter the nucleus of the cell and bind to DNA (such that it is able to regulate gene expression).
What are nuclear receptor superfamilies organized based off of? What kind of nuclear receptor is vitamin D receptor?
Nuclear receptor superfamilies are organized based off of what they bind to - there are nuclear receptors which bind steroids, nuclear receptors which bind fatty acids, receptors that bind proteins, etc.
If it is not known what these receptors bind to, they are called orphan receptors.
Vitamin D receptor is a steroid hormone receptor.
Where is the vitamin D receptor found in the body?
Vitamin D receptors are found in almost every single tissue in the body. This means that vitamin D is probably pretty important
Explain the pathway by which calcitriol (and the vitamin D receptor with RXR) is able to cause changes in gene expression (such that proteins are formed).
Circulating vit D will cross the cell membrane from the blood and bind the vitamin D receptor. It’s usually attached to a corepressor. Once the vit D binds, the co-repressor is removed and the vitamin D receptor is able to form a heterodimer with retinoic X receptor. In order for RXR to be able to heterodimerize, it must first unbind its attached co-repressor. It has to bind retinoic acid such that this enables retinoic X receptor and vitamin D receptor to heterodimerize. When this happens, it is able to bind to the vitamin D response element. RXR and VDR are able to recruit co-activators which are then able to recruit things like the transcriptional machinery. This will then lead to the activation of RNA polymerase which begins to make RNA. RNA transcripts are then processed and sent to the cytosol for translation by ribosomes.
How many human genes are modulated by the vitamin D receptor and active form vitamin D?
With the vitamin D receptor alone (activated with calcitriol = 1α,25(OH)2-D3), you get a change of about 3000 genes (out of 22,000 total genes which lead to protein in the human genome).
Explain the pathway by which the final forms of vitamin D3 is made from 7-dehydrocholesterol, and what the each final form of vitamin D does after it is formed.
In the skin, 7-dehydrocholesterol is turned into vitamin D3 through the use of sunlight and then heat. This vitamin D3 then goes into the blood to the liver to make the single hydroxylated intermediate (the 25(OH)-D3), which can circulate in the blood.
If the individual (which this vitamin D is in) is pregnant, this intermediate will cross the placenta to help the baby form vitamin D (for bones).
This hydroxylated intermediate, in the blood, will go to the kidney and convert into 1α,25(OH)2-D3 and 24R,25(OH)2-D3.
The active form of vitamin D (1α,25(OH)2-D3) will circulate back through the blood and then it is going to bind to vitamin D receptors in about 37 different tissues to cause a bunch of different responses. In the intestines it will cause absorption of Ca2+, in the bones it will cause mobilization of Ca2+ and phosphate, and in the kidneys it will cause reabsorption of Ca2+
After calcium levels have been increased by 24R,25(OH)2-D3, what occurs? What does parathyroid hormone do in this response as well?
Calcium is going to signal the parathyroid to inhibit production of parathyroid hormone. In this same pathway, parathyroid hormone is going to signal to the kidneys to active a specific hydroxylase which will lead to the production of both 1α,25(OH)2-D3 and 24R,25(OH)2-D3. 24R,25(OH)2-D3 will then signal to the parathyroid to inhibit secretion of parathyroid hormone, and will signal to the intestines, bones, and kidneys to increase extracellular calcium levels.
In addition to signaling the bones, intestines, and kidney to increase extracellular calcium levels, what other roles does 24R,25(OH)2-D3 have?
24R,25(OH)2-D3 plays a role in chondrocytes as well as in forming fracture healing callous
What specific tissues does 1α,25(OH)2-D3 (active form of vitamin D) act on?
- beta cells of the pancreas to stimulate insulin secretion
- In bone marrow it promotes cell differentiation (important for monocytes and macrophages (immune cells/white blood cells) as well as formation of osteoclasts through osteoblast activation).
- In the immune system it will activate B-cells and T-cells (affecting your innate immunity and memory cells). In the innate immune system it will stimulate synthesis of antimicrobial peptides (which help you combat microbes - bacteria/viruses). In the adaptive immune system it will promote the formation of white blood cells (for immunity).
- In cancer cells (cells from uncontrolled cell growth) it can actually inhibit proliferation and promote differentiation (essentially giving the cells jobs - changing gene expression of the cell to become another type of cell). Stem cells (like cancer cells) are the cells that normally divide rapidly in normal individuals, thus causing them to differentiate (or have jobs) makes them not divide as rapidly.
- In the cardiovascular system it is going to help with the renin-angiotensin regulation (for blood pressure). It is also important for heart muscular function.
- Its also important for muscle (muscular) strength and normal muscular development.
What does 1α,25(OH)2-D3 do to the intestines, bones, and kidneys?
Intestines: stimulate calcium and phosphate absorption
Bones: stimulate both bone formation and reabsorption. This balance between osteoblasts and osteoclasts is going to be dictated by a bunch of different factors, as well as the amount of calcium that you have.
Kidneys: stimulate the reabsorption of calcium and phosphate to help bring those back into circulation. This is very similar to parathyroid hormone, however parathyroid hormone was really only for reabsorption of calcium, not as much for phosphate.
Mutation of the vitamin D receptor can result in _____. Explain the characteristics of this disease.
Alopecia is loss of hair (usually through some kind of genetic issue, or through vitamin D/vitamin D receptor). This is because the vitamin D receptor is in the hair follicle - so if you have issues with the vitamin D receptor it can cause weakness in the hair follicle, and this can stop the growth or the ability of the hair follicle to proliferate properly.
Since the vitamin D receptor (receptor for 1α,25(OH)2-D3) is present in a lot of different tissues, what can issues with the receptor cause?
It can lead to osteoporosis for bones, T1D, increased prevalence of infection and autoimmune disorders, increased risk of heart failure and high blood pressure, muscular weakness, as well as an increase risk of calcium deficiency
What form of vitamin D is prescribed in the US to treat _____.
Psoriasis, secondary hyperparathyroidism, and chronic renal disease
