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Five things Ca+2 is important for
1. Cofactor for enzymes involved in blood clotting
2. Muscle contraction
3. Structure of bone and teeth (99% of Ca+2 is bound to bone or teeth)
4. Nervous transmission (secretion of neurotransmitters)
5. Functions of most cells, secretion.
Generally, what ion is needed for stimulus secretion coupling? What is the exception?
↑Ca+2 = ↑secretion
exception: ↑Ca+2 = ↓PTH (need Mg for PTH secretion)
Intracellular Ca+2: conc + where stored?
- [Ca+2]cytosol is approximately 1/10,000th of extracellular concentration
- Stored in mitochondria and endoplasmic reticulum
Extracellular Ca+2: conc + amount free vs bound
- Ca+2 normally ranges from 8.5-10 mg/dL in the blood (very high)
- ~ 48% of Ca+2 in the blood is in a free, ionized form. ~46% bound to protein (serum albumin) and 6% is complexed into salt
-Only the free, ionized Ca+2 is available to be taken up by cells
Calcium and Phosphorous relationship
-Ca+2 and PO4- tightly regulated (more PO4- = less Ca+2)
-PO4- is an essential mineral necessary for synthesis of ATP, cAMP, nucleic acids, etc
Ca+2 Homeostasis: Pathway through the body
1000mg in through diet → 350mg absorbed into body → extracellular fluid (1000mg at a time) → 500mg deposited into bone, but 500mg also comes out → 150mg secreted into colon (+ 650mg that shot straight through at beginning) and 200mg into urinary excretion
Ca+2 and Bone relationship
- 99% of Ca+2 is found in the bone
- Most is found in hydroxyapetite crystals
- Very little Ca+2 can be released from the bone, though it is the major reservoir of Ca+2 in the body
Major Hormones in Ca+2 metabolism
1. *Parathyroid Hormone (PTH)- parathyroid glands. polypeptide. hypercalcemic
2. *1,25 dihydroxycholecalciferol (vitamin D, calcitriol)- synthesized by skin, liver, kidney. hypercalcemic
3. Calcitonin- C cells of thyroid gland. polypeptide. hypocalcemic
Which Ca+2 hormones are most essential?
without PTH you will die within a day, only hormone like this. why? we usually need to ↑ Ca+2 more than ↓ it. too much Ca+2 is not detrimental right away. too little Ca+2 and you could die in a few hours
PTH: #aa and processing
-PreproPTH: first is a prohormone with a signal peptide and cryptic region (we know more about the processing of this hormone than any other)
Regulation of PTH secretion
↑ serum [Ca+2] , ↓ [PTH]
↓ serum [Ca+2] , ↑ [PTH]
Vitamin D- inhibits (neg feedback)
Biosynthesis of PTH
- CaR (GPCR)- linked to PLC via Gq, adenlyl cyclase via Gi (decreases cAMP)
- Ca+2 inhibits txn of PTH gene AND inhibits secretion of PTH
- Ca+2 inhibits secretion, PTH secretion dependent of Mg+2
only cell where Mg+2 is required for secretion (all others = Ca+2)
Sites of PTH action: direct vs indirect
1. Bone = direct. ↑ Ca+2 release from bone. ↑ recruitment of osteoclasts and bone turnover (matrix metalloproteinases- enzymes break down bone)
2. Kidney = direct. ↑ reabsorption of Ca+2. ↑ renal absorption of Ca+2 and ↑ PO4- excretion
3. Intestine = indirect. ↑ synthesis of Vitamin D which then acts on intestine. ↑ 1,25 (OH)2D3 levels
How PTH acts on Bone
-PTH action leaders to the stimulation of resting osteoclasts to ↑ bone turnover and ↑ serum Ca+2
-BUT! PTH actually acts on osteoblasts, which produce a chemical mediator (RANKL- receptor activator of NF kappa B ligand) that acts to stimulate osteoclasts
Mechanism of Action of PTH
- PTH acts on cells by binding to cell surface G-protein coupled receptors
- The PTH receptor signals through Gs which is linked to adenylyl cyclase
- PTH ↑ intracellular cAMP
end-organ resistance. congenital disease of G protein coupled to PTH receptor
albright hereditary osteodystrophy
-end-organ resistance to PTH
-epiphyses are fused (usually there is a layer of cartilage)
-obesity phenotype... we don't know why
Parathyroid Hormone Related Protein (PTHrP): Structure
-related to PTH; product of a separate gene
-first 6 aa identical to PTH
-larger than PTH; approx 140-175 aa depending on species
PTHrP: Physiological Role
- widely expressed in normal and malignant tissues
- plays a role in normal development, regulating proliferation and differentiation of chondrocytes (cartilage), and lung development
- also regulates placental Ca+2 transport
PTHrP: Role with Lungs
-alveolar interstitial cells make PTHrP receptor and make leptin.
-leptin acts on alveolar cells to ↑ production of PTHrP, which then acts on the alv int cells to make more leptin (paracrine positive feedback loop). leptin is important for the production of surfactant
-glucocorticoid (dexamethasone) → helps infant produce surfactant (acts by increasing production of the PTHrP receptor and also leptin)
- PTHrP is often highly expressed by tumor cells (people with cancer often have elevated Ca+2)
- PTHrp (when high) binds to and activates the PTH receptor (squamous cell lung carcinoma)
Regulators of Vitamin D Biosynthesis
1. Serum Ca+2 ↓ , Vit D ↑
2. PTH- upregulates expression of 1α-hydroxylase by kidney (essential)
3. Ultraviolet light- essential (need at least 15 min per day)
Biosynthesis of Vit D
-Liver- 25 hydroxylase (constituitively expressed)
-Kidney- 1α hydroxylase (regulated by PTH)
-7-Dehydrocholesterol (UV light, skin) → Previtamin D3 (Heat, skin) → Vitamin D3 [or from diet] (25 hydroxylase, Liver) → 25-OH-D3 (PTH on 1α hydroxylase, kidney) → 1,25-(OH)2-D3 aka 1,25 dihydroxycholecalciferol
Rate Limiting Step of Vit D synthesis?
UV light if you make it. If you get it from diet, then PTH action on 1α hydroxylase
Vit D actions on Bone
promotes differentiation of osteoclasts from pre-osteoclasts (↑ PTH receptor in osteoblasts. also direct on osteoclasts)
Mechanism of Action of Vitamin D
-A steroid hormone and it acts via nuclear hormone receptors to regulate gene expression. Vitamin D can induce or repress gene expression (VDR-RXR)
-Without Vit D to make PTH receptor, PTH cannot act
Vitamin D induces synthesis of:
1. calcium binding proteins (calbindins; CaBP) within the cell (more bp in cell, less free Ca+2, larger gradient) which sequester Ca+2 in gut epithelial cells
2. Ca+2 ATPase targeted to the basolateral surface
3. Ca+2 channels targeted to the apical surface (brush border) TRPV6 channels (transient receptor cation channel V6)
Calcitonin: produced by what? action?
-C cells (parafollicular cells) in the thyroid gland
- CT inhibits PTH actions on bone
- ↓ PO4- and ↓ Ca+2 reabsorption (we don't know why ↓ PO4-)
Review: Ca+2 hormones- actions, what makes them, where they act
1. Parathyroid Hormone: parathyroid glands. hypercalcemic. kidney, bone.
2. Calcitonin: C cells of thyroid gland. hypocalcemic. bone, kidney
3. 1,25 dihydroxycholecalciferol (vit D): synthesized by skin, liver, kidney. hypercalcemic. intestine, bone.
**Other Regulators of Calcium Metabolism
1. Cortisol- ↑ PTH
2. Prolactin- can make lactating woman hypocalcemic (milk proteins bind Ca+2)
3. Growth Hormone and IGFs- bone growth/synthesis
4. Thyroid Hormone- skeletal development
5. Estrogen- bone deterioration (osteoporosis)
abnormal mineralization of bone and cartilage. caused by:
1. Vitamin D deficiency (hereditary disorders in 1α hydroxlase, bow-legged)
2. Mutations in VDR
abnormal mineralization of bone and cartilage.
Vitamin D deficiency as an adult (ex: people that don't go outside enough)
Factors known to cause osteoporosis
1. family history
2. low dietary intake of calcium
3. use of some medications such as prednisone
4. certain hormonal disorders such as hyperthyroidism, hyperparathyroidsm, and Cushing's disease
5. Other diseases such as chronic liver disease and intestinal disorders
Most effective way to regain lost bone mineral?
Estrogen: Now controversial based on new clinical trials (HRT- Hormone replacement therapy)
-HRT less common now because found that it ↑ cardiovascular disease and ↑ breast cancer
-instead, trying selective estrogen receptor modulators (SERMs)
Fish! do they have bone?
-Many fishes lack true bone (cartilagenous fishes)
-Bony fishes (teleosts) have acellular bone.
Bony fishes: bone structure
Layers of cells around periphery synthesize bone. (they don't absorb/turnover bone)
Hollow layer, then PO4-/Ca+2 deposited, then cellular layer
Most important reservoir for Ca+2 in fishes?
-Soft tissues, surrounding waters are a more important source of circulating Ca+2 than the skeleton
(They can take up Ca+2 all the time, so they don't need stores like we do)
Fish organs related to Ca+2
Gills and intestine: Ca+2 uptake
Kidney: excretes Ca+2 and other divalent ions
Scales: another area where Ca+2 can be mobilized
Do fish have parathyroid glands?
no, but they do have PTH related peptides
-Parathyroids only present in tetrapods
Fishes: primary regulation of serum Ca+2
pituitary (hypercalcemic) and the Corpuscles of Stannius (hypocalcemic)
Do fishes have Calcitonin?
Fishes have ultimobrachial glands (same precursor as C cells) that produce calcitonin, but there is no correlation between calcium levels and calcitonin
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