Flashcards in Hormones in Ca Regulation Deck (98):
Where and in what form is most Ca in the body stored?
bones as hydroxyapatite salt
What are the three major fractions of Ca in the plasma?
-Protein bound calcium to albumin
-Ca complexed to citrate and phosphate forming soluble complexes
What is the role of Ca in the coagulation cascade?
Initial platelet plug formation and most steps of blood coagulation
What is the role of Ca in the CNS/PNS?
Important for neuromuscular excitability
What are the two major intracellular effects of Ca?
-Second messenger (Gq proteins)
-Cofactor for various enzymes
What are the three major hormones that play a role in Ca metabolism?
Where are the parathyroid glands located?
the top and bottom of the lateral lobes of
What are the cells that are in the parathyroid that secretion PTH?
What are the roles (generally) of PTH?
Plays a major role in bone remodeling, and extracellular Ca homeostasis
What is the role of PTH at the level of the kidney?
Regulates the renal excretion of phosphate and the activation of vitamin D
How much PTH is stored by the chief cells, as opposed to synthesized on demand?
Relatively small amount are stored
At what Ca levels (relative) is PTH secreted?
Low Ca levels
What is the precursor form of PTH? What organelle of the chief cells secrete this?
What is the "leader sequence" found on preproPTH?
A sequence of about 25 amino acids in its N terminus that serves as a place for cleavage, occurring within minutes of pre-proPTH synthesis
Where does the cleavage of preproPTH happen, and where does proPTH go after this occurs?
As it exits the rER, with proPTH then exiting to the Golgi
What happens to proPTH in the Golgi?
Trypsin like enzymes cleave a *hexapeptide* from the N terminal end of proPTH, converting proPTH into active PTH
Where is PTH stored in chief cells? What causes its release?
Into secretory granules in the Golgi complex
Low extracellular Ca causes deactivation of the calcium-sensing receptors (CaR)
What is the sensor on chief cells that activates the synthesis of PTH when low Ca levels are present in the serum? What type of sensor is this? How long does it take for PTH to be secreted?
PTH is released within seconds
What does it mean that both PTH synthesis and release occurs in a negative feedback manner?
High calcium suppresses PTH secretion, while low calcium stimulates hormone release
What is the effect of vitamin D on PTH? How?
Reduces PTH gene expression by suppressing PTH mRNA transcription and stability
What is the effect of phosphate on PTH?
Activates CaR, and thus decreases PTH release
Where are CaR sensors present? (3)
Thyroidal C cells
What are the intracellular steps that occur with CaR activation? What specific part of this pathway causes PTH degradation?
IP3 and DAG lead to the activation of PLC and Ca release from the sER
Leukotriene generation triggers the degradation of PTH
Persistent hypercalcemia can cause what percent of PTH degradation within the cell?
What happens to the CaR when there is hypocalcemia?
The Ca2+ sensor is in a relaxed conformational state and cannot activate the second
messengers involved in the degradation of PTH.
What is the major receptor on target cells for PTH?
What are the two intracellular pathways that are activated with PTHR1 activation?
Gs and Gq
What happens intracellularly with Gs activation?
Increase in cAMP and activation of PKA. This phosphorylates and activates enzymes
What happens intracellularly with Gq activation?
PLC activation results in the formation of DAG and IP3, which in turn leads to the activation of PKC and the release of intracellular Ca
What allows target cells of PTH to switch between Gs and Gq pathways?
The cell is able to switch from one pathway to the other by using Na+/H+ exchanger regulatory factor [NHERF1]
What are the two primary targets of PTH? What
What other hormone, besides PTH, can activate bone osteoblasts and the kidney? How does it do this?
PTH-related protein (PTHrP)
Shares 13 amino acid sequence with PTH (although is a product of a separate gene)
What is the effect of PTH and PTHrP on the kidney and osteoblasts?
Increasing Ca reabsorption in the kidney, and increase Ca mobilization from bone
What is the effect of PTH on the intestines?
Increases intestinal reabsorption of Ca (via Vitamin D)
What, besides increasing renal reabsorption of Ca, does PTH do in the kidney? (2)
Stimulates phosphate excretion and the activity of 1α-hydroxylase (for Vit D synthesis)
How does PTH binding to receptors in the kidney lead to increased Ca uptake?
PTH stimulates the insertion and opening of a Ca2+ channel on the apical
membrane, facilitating the entry of Ca2+ into the cell
What is the proteins that binds Ca once it enters the cytosol of kidney epithelial cells from the kidney? What does this protein do? What vitamin is this protein dependent on?
cytosolic diffusion of Ca2+ from the apical influx to the basolateral efflux sites
What are the two proteins that secrete Ca into the bloodstream from kidney epithelial cells?
Na+/Ca2+ exchanger and a Ca2+- adenosine triphosphatase (ATPase)
Vitamin D activates what protein on the kidney epithelial cells to stimulate Ca release into the circulation?
How does PTH decrease renal phosphate reabsorption?
decreasing the expression of type II Na+/PO42− cotransporter
What are the four types of cells found in bone?
-Osteogenic (osteoprogenitor) cells
What is the role of Osteogenic (osteoprogenitor) cells?
are undifferentiated cells with a high mitotic activity
and can develop into osteoblasts
What are the only cells in the bone that maintain their ability to divide?
Osteogenic (osteoprogenitor) cells
What is the role of osteoblasts in bone? Do they express PTH receptors?
They are involved in bone formation and mineralization. They express
What is the role of osteocytes in bone?
Osteocytes are trapped osteoblasts in bone matrix that function to maintain the bone matrix
What are the two main components of the bone matrix?
and hydroxyapatite (calcium rich crystals)
What is the role of osteoclasts in bone? What cells are they derived from?
cells developed from macrophages/monocytes that secrete acids and enzymes to dissolve the bone matrix
True or false: bone is constantly undergoing remodeling
What cells in bone have PTHR1 receptors? What does this trigger?
This triggers synthesis of RANKL (receptor activator of nuclear factor NF-kB ligand)
What is RANKL? Where is this found? What does this bind to?
receptor activator of nuclear factor NF-kB ligand
Found within osteoblasts
binds to RANK receptor on osteoclastic precursors
What stimulates the maturation of osteoclasts?
RANKL binds to RANK receptor in osteoclasts precursors,
What is osteoprotegerin and what is its role?
A protein secreted by osteoblasts that prevents the binding between RANK and RANKL, thereby inhibiting the osteoclastic bone resorption
What is the effect of PTH and glucocorticoids on the bone?
PTH and glucocorticoids decrease the production of osteoprotegerin
What is the effect of estrogen on the bone?
Increases the expression of osteoprotegerin, thereby inhibiting osteoclast maturation
What is the protein found on the surface of bone that osteoclasts attach to? What does this form?
This forms an isolated extracellular space between themselves and the bone
surface that functions as a lysosome
What is the transporter on the osteoclast cells that allows for the breakdown of bone? What does this do to encourage bone breakdown?
Generates an acidic environment (pH =4)
Where does the Ca and phosphate go once it is broken down by osteoclasts?
Undergoes transcytosis to be secreted into the blood
What is the clinical marker for bone breakdown? Why?
Alk phos, since this is secreted along with Ca and phosphate by osteoclasts during the breakdown of bone
What can result in hyperparathyroidism?
-Chronic renal failure
How can chronic renal failure lead to the hyperparathyroidism?
Reduces vit D and Ca reabsorption, making the parathyroid gland resistant to both the vitamin D and Ca negative feedback of PTH release
What happens to [Ca] in the serum and the urine with hyperparathyroidism? What about plasma [phosphate]?
What is the sequelae of hyperparathyroidism on the kidneys?
What is the only vitamin that is not required in the diet?
What are the two forms of Vitamin D?
-vitamin D2 (ergocalciferol)
-vitamin D3 (cholecalciferol).
UV irradiation of what two molecules leads to the development of Vit D2 and D3 respectively?
What is the name of the active form of vitamin D?
Calcitriol (1,25 D3)
What are the steps of calcitriol synthesis from 7-dehydrocholesterol?
1. UV light irradiates the skin to form provit D
2. Provit D3 isomerized to D3 and transported to the liver
3. Liver converts to 25-hydroxyvit D3
4. Kidney converts to 1,25-D3
What is the protein that transports Vit D3 from the skin to the liver?
Vitamin D binding protein
What happens to Vit D3 in the liver?
Converted to 25-hydroxyvitamin D3
What is the major circulating form of Vit D?
What is the enzyme in the kidney that converts 25-hydroxyvit D3 to 1,25 D3?
How is the production of calcitriol regulated?
Negative feedback regulation by plasma Ca--An increase in plasma Ca2+ levels inhibits the hydroxylation at C-1 and
favors hydroxylation at C-24, leading to the synthesis of an inactive form of vitamin
How does PTH stimulate the formation of Vitamin D?
Simulates that activity of 1α-
True or false: Calcitriol can be also synthesized from vitamin D2 (ergosterol) when obtained
from the diet.
What are the four target organs of Vit D?
What is the effect of Vit D on the kidneys?
Facilitate PTH-mediated calcium reabsorption in the distal kidney tubules
What is the effect of Vit D on the parathyroid gland?
Suppress the synthesis
and release of PTH
What is the effect of Vit D on bones?
Regulate bone resorption and formation
Does calcitriol exert its effect through cell membrane receptors, nuclear receptors, or both? What is the significance of this?
Both, meaning it can exerts its effects through both increased gene transcription, and nongenomic mechanisms
How does calcitriol exert its effects in the intestines?
Regulates the transcription of TRPV6 and the Na/Ca exchanger on intestinal epithelial cells
What is the channel that allows calcium into the intestinal epithelial cells from the lumen of the intestines?
Transient receptor potential vanilloid channel type 6 (TRPV6)
What is the channel that allows Ca out of the basolateral side of the intestinal epithelium into the bloodstream?
Plasma membrane Calcium ATPase and the Na/Ca exchanger
What is the effect of Vitamin D on bone?
It stimulates bone resorption (osteoclast formation) causing mobilization of Ca
What are the three effects of excess vitamin D?
-calcinosis of soft tissues
-Deposition of Ca and phosphate in the kidney
What are the genetic disorders that can lead to vitamin D deficiency?
mutations in 1α-hydroxylase
What are the two forms of vitamin D deficiency in children/adults?
Rickets in children
Osteomalacia in adults
What are the classic findings in Rickets?
Bowing of the weight bearing bones
What type of hormone is calcitonin?
Where is calcitonin produced? What is it initially produced as?
C cells of the thyroid gland as procalcitonin
What are the receptors that trigger calcitonin release?
What is the MOA of calcitonin in the bones?
inhibits bone resorption by decreasing osteoclast motility, and inhibits Carbonic anhydrase activity
What is the MOA of calcitonin in the kidneys?
Increases urinary Ca excretion by inhibiting the renal tubular Ca reabsorption via G proteins
True or false: There are no significant clinical correlations associated with calcitonin excess or deficiency
True--calcitonin does not appear critical for the regulation of calcium homeostasis
What is calcistat?
The multi organ regulation of calcium homeostasis exists as a big systemic regulatory
network referred to as calcistat.
What is the normal range of Ca serum levels (in mM)? Above what level is Ca resorption slowed, and excretion increased?
Above 1.3 mM
What is the plant version of vitamin D?
What is the circulating form of vitamin D? Active form?
Circulating = 25, hydroxy
Active = 1,25 dihyrdroxy