Cell Signaling Pathways: Steroid hormones (Vitamin D3) Flashcards by Olivia Bellantoni

is vitamin D a hormone or vitamin

BOTH

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what are sources of vitamin D

bare skin exposure to sun 5-10 minutes 2-3 times per week and fish oils and fortified foods and dairy products

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how does vitamin D reduce caries

produces cathelicidin and defensins proteins that have antibacterial effects to fight bacteria that cause cavities. secreted in GCF

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what is the biologically active form of vitamin D

1alpha,25 (OH)2D3, cholecalciferol = Vitamin D3

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describe the biosynthesis of vitamin D3

cholesterol is a precursor
-UVB exposure creates previtamin D3 which undergoes thermally induced rearrangment to vitamin D3
vitamin D3 is transported to the liver where it is hydroxylated by 25-hydroxylase producing 25(OH)D3.
-25(OH)D3 is hydroxylated in the kidneys one more time to 1alpha,25(OH)2D3

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what is the main circulating form of vitamin D

25(OH)D3

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what organ provides the majority of cirulating 1,25(OH)2D3

the kidney

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what synthesizes 1,25 (OH)2D3 for autocrine and paracrine use

the skin and a variety of immune cells and some maligant cells

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how is 25(OH)D3 transported in the serum

by vitamin D binding protein (DBP) or transcalciferin (TC)

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what do serum levels of 25(OH)D3 indicate

how much vitamin D is entering the host

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what is ergocalciferol/vitamin D2 and what are the issues with it

a plant/fungi form most commonly found in dietary supplements and many fortified foods
- it is less absorbable, less potent and shorter acting

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what substances undergo the conversion of 25(OH)D3 to 1aplha,25(OH)2D3

ergocalciferol and cholecalciferol

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what is the common name for 1,25(OH)2D3

calcitriol

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how does 1,25(OH)2D3 exert cellular actions

binding to the vitamin D receptor in target cells

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why is the 1,25(OH)2D3 form the biologically active form of Vitamin D

because it has the highest affinity for the vitamin D receptor by far

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Where is the vitamin D receptor found

widely distributed among tissues not just classic targets of vitamin D

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what happens when 1,25(OH)2D3 binds to the vitamin D receptor

VDR forms a heterodimeric complex with other nuclear hormone receptors, particularly the retinoid x receptor (RXR)
-heterodimeric complex binds to DNA promotor sequences containing the VDRE (vitamin D response element) sequences in genes it regulates
co-activators complex with the activated VDR/RXR heterodimers to recruit the proteins required for transcription such as RNA polymerase 2 to the transcription start site

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what are the 2 domains on the VDR

hormone binding domain and the DNA binding domain

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describe vitamin D3 induced calcium absorption in the gut

calcium enters the luminal surface of the brush border through a TRPV6 calcium channel
-calcium is complexed with calbindin transport proteins where it can be exchanged for sodium on the basolateral surface by the calcium ATPase, undergo transcellular transport between endocytes, or exocytosed by lysosomal vesicles

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what is the TRPV6 calcium channel controlled by

vitamin D3

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what happens to vitamin D synthesis when Calcium is low

vitamin D synthesis is increased, increased expression of TRPV6 channels, and increase in CaBP proteins

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what genes are affected by the vitamin D receptor

-genes by osteoblasts needed to form bone:collagen, alkaline phosphatase
- genes positively regulating intestinal transcellular calcium transport: TRPV6, the calbindins, the CaATPase

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what does 1,25 (OH)2D3 induce the expression of

RANKL which required for osteoclast formation
-antimicrobial peptides produced by salivary glands and mucosal epithelium such as defensins and cathelicidins

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what produces defensins and cathelicidins and what do they do

-they are produced by salivary gland and mucosal epithelium
- they have broad antimicrobial activity against gram negative and gram positive bacteria and are effective against oral microorganisms such as strep mutans, porphyromonas gingivalis, and actinobacillus actinomycetemcomitans

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what is the major role of vitamin D3

to control calcium homeostasis in circulation

what causes rickets

severe vitamin d deficiency

what does vitamin D3 play significant roles in the formation of

muscle, immune function. prevention of colon, prostate and breast cancer, diabetes, heart disease, HTN, and MS

what are the deficient, insufficient, and normal ranges for vitamin D

deficient: below 20 ng/ml insufficient 20-29 ng/ml normal: above 30 ng/ml

what are the symptoms of vitamin D deficiency

-costochondral junction (rachitic rosary) - deformities of the back and bowing of the legs - softened calvarium -parietal flattening -frontal bossing -delayed eruption of permanent dentition and enamel defects

what is nutritional rickets and where is it most common

-vitamin D, calcium, or phosphate deficiency - most common in countries that dont fortify their food and have low exposure to sunlight - also common in infants who do not have vitamin D supplementation

what happens in type 1 rickets and when is it diagnosed, and how is it treated

-manifests by age 2 -defects in 25(OH)D 1-hydrolase - low circulating levels of 1,25 (OH)2D3 -treated with massive doses of vitamin D or lower doses of 1,25(OH)2D3

what is type 2 rickets, when is it diagnosed, symptoms and how is it treated

-normal or high circulating levels of 1,25(OH2)D3, receptor deficiency - normal at birth, age 2 - symptoms: alopecia, multiple milia, epidermal cysts and oligodontia -treated with high dose of 1,25(OH)2D3 and up to 3 gm of calcium per day

what is osteomalacia

softening of the bones due to inadequate levels of calcium and phosphate which are commonly due to vitamin D deficiency

what are the oral manifestations of rickets

-developmental abnormalities of dentin and enamel - delayed eruption - misalignment of teeth in the jaw - high caries index - enamel hypoplasia

explain the relationship between sunlight exposure and risk of dental caries

increased sunlight exposure decreases the risk for dental caries

what happens in the hereditary vitamin D3 resistant rickets

amino acid mutations in VDR DNA-binding domain or the ligand binding domain

what is different in the symptoms of a mutation in the DBD region vs the LBD region in HVDRR

HVDRR patients with mutations in the DBD have alopecia

what is psoriasis and what is used to treat it

- an immune mediated disease affecting skin - tx:topical ointments containing coal tar, corticosteroids, vitamin D3, or retinoids. OR phototherapy, or biologics (pills) such as enbrel and remicade (TNF alpha inhibitors which reduce inflammation) stelara (inhibits IL-12 and IL-23)

what organs play a role in calcium homeostasis

skeleton, gut and kidney

what senses calcium levels

the parathyroid gland through the calcium sensing receptor (CaSR)

what produces PTH

chief cells of the parathyroid

what produces calcitonin

parafollicular cells of the thyroid

what does PTH do

increases calcium levels

what does calcitonin do

decreases calcium levels

what does PTH do to phosphate

increase in phosphate excretion through the urine, but enhances uptake of phosphate from the intestine and skeleton into circulation. results in net decrease of serum phosphate

what should serum ionized calcium be

4.5-5.2 mg/dl

what should serum total calcium be

8.8-10 mg/dl

what should serum phosphate levels be

2.5-4.5 mg/dl

what should serum magnesium levels be

1.7-2.6 mg/dl

what is a physical manifestation of low calcium levels

oral tingling sensation in and around the mouth and lips

what part of calcium is the physiologically actice compartment

only the free (ionized) form of calcium

what is the precursor that PTH is derived from

Pre-Pro-PTH

what are the PTH receptors

PTH1R and PTH2R

what is PTHrP

a closely related homolog to PTH which plays a role in tooth eruption and endochondral bone formation

what does PTH1R bind

PTH and PTHrP

what stimulates 1,25(OH)2D3 by the kidney

only PTH NOT PTHrP

what is the CaSR activated by

extracellular Ca2+ and di-, tri-, or polyvalent cations, polyamines, and aromatic and other L-amino acids

What type of receptor is the Calcium sensing receptor (CaSR)

a GPCR

what pathway does the CaSR initiate when Ca2+ concentration is low? high?

low- activates cAMP to stimulate PTH secretion high- activates PLC to inhibit PTH secretion

what does the CaSR play a role in

-regulates the release of PTH - in the kidney it controls of reabsorption of Ca2+, phosphate, Na+ and water

what is the mechanism of action with calcium sensing via the CaSR

low calcium stimulates PTH release which increases 1,25(OH)2D3 which stimulates Ca2+ release from bone which stimulates Ca2+ absorption in the gut

what is the common name for vitamin D2

ergocalciferol