Endocrine Exam 410B Instruction 4-5

3 forms of calcium in plasma

1. Free ionized calcium ( Ca2 + ) , 45 % free ( in plasma ) 2. Protein - bound calcium 3. Calcium complexed with citrate or oxalate

Vitamin D is a vitamin , Can be obtained from the diet

1. Vitamin D₂ - vegetables 2. Vitamin D3 - the liver of fishes like cod and halibut , eggs , fortified milk and bread

calbindin effect

1.Buffer cytosolic Ca² + to keep favorable Ca² + -gradient 2.Allows cell to absorb large amounts of Ca² + , while keeping free cytosolic [ Ca2 + ] low

Hypercalcemia of Malignancy (2)

1.Local osteolytic hypercalcemia 2.Humoral Hypercalcemia of Malignancy

Vitamin D intoxication

1.vit D synthesis by lymphomas or Vit D overdose 2. - 100,000 Units / day is required to produce hypercalcemia

Parathyroid Glands Location

4 pea shaped glands on surface of thyroid gland( posterior side)

Other regulators of insulin release :

Amino acids Neural factors ( acetylcholine ... ) iii.ß - adrenergic receptors iv.a - adrenergic receptors v.Exercise Feeding

The parathyroid gland is ______________, not _________________ related to the thyroid gland .

Anatomically, not functionally

How vitamin D enhances Ca² + absorption via transcellular pathway in duodenum

Ca2 + enters cell via Ca² + channels Ca² + binds to several binding proteins , particularly calbindin Ca² + is transported across basolateral membrane by Ca² + pump : Na - Ca exchanger

Vitamin D deficiency rickets

Chikdhoodmbone disorder- low mineralization of bones- vit D disorder Several years of very low dietary intake is required before deficiency develops

Parathyroid Glands

Composed of chief cells that synthesize and secrete parathyroid hormone ( PTH )

PTH fragments: N - terminal

Contains all biological activity and Rapidly hydrolyzed

What is major source of calcium

Dairy products(diet)

Glucose is transported into ß - cells via

GLUT2 transporters

__________stimulates insulin release from B - cells .

Glucose

Parathyroid - independent Hypercalcemia (2)

Hypercalcemia of Malignancy and Vitamin D intoxication

Calcitonin __________ bone resorption

Imhibits

Insulin synthesized as a pre - prohormone

In trans - Golgi , proteases cleave C peptide to form insulin ( A , B ) . Insulin ( B , A ) is the A - peptide linked to the B - peptide by bisulfide bonds Insulin ( A , B ) , proinsulin ( B , C , A ) , and C peptide are packaged into secretory vesicles .

Two ways vitamin D increases calcification of bone

Indirect: increased absorption of Ca² + in intestine and kidney Direct: mobilize Ca² + out of bone 2.promote development of osteoclasts from precursor cells 3.stimulate osteoblasts to produce alkaline phosphatase collagenase , plasminogen activator

PO4 3- and 1 , 25- ( OH ) ₂D _______ 1a - hydroxylase

Inhibit

PTH ________ synthesis and secretion of OPG from osteoblasts

Inhibits

C peptide is a good measure of insulin secretion because

Insulin removed by liver, C peptide is not

PTH fragments: C - terminal

Long half life and Complicates measurements of PTH release .

Familial Hypercalcemic Hypocalciuria ( FHH )

Mild hypercalcemia caused by loss of function mutations of the Ca² + sensing receptor ( CASR )

Will Vitamin D stimulate phosphorylation of the NaPi ?

NO

3 types of bone cells

Osteoblasts, Osteocytes, Osteoclasts

Bone Resorption by the Osteoclast

Osteoclasts move along surface of bone and secrete acids into lacuna that provide optimal conditions for the action of lysosomal proteases to dissolve bone

Actions of Vitamin D on Bone

Overall effect of Vitamin D is to increase calcification of bone .

Calcium inhibits VitD by inhibiting ___

PTH

How PTH inhibits PO4³- reabsorption mainly in proximal tubules

PTH causes NaPi cotransporters to be sequestered within endocytic vesicles , delivered to lysosomes where they undergo proteolysis

Process of bone remodeling by osteoclasts and osteoblasts

PTH stimulates osteoblasts to secrete RANK ligand and Macrophage colony stimulating factor ( M - CSF ) RANK stimulate osteoclast differentiation and osteoclast activity M - CSF induces stem cells to differentiate into osteoclast precursors , mononuclear osteoclasts , and mature multinucleated osteoclasts .

How PTH stimulates Ca² + reabsorption in the distal tubules

PTH stimulates the insertion and opening of the apical Ca² + channel, Ca² + binds calbindin, Ca² + is transported out of the cell by a Na / Ca exchanger

Hypercalcemia types

Parathyroid - dependent , Primary Hyperparathyroidism ( parathyroid adenoma Excess PTH - is most often due to parathyroid adenomas 75 80 % Familial Hypercalcemic Hypocalciuria ( FHH ) .

major organ governing calcium homeostasis

Parathyroid gland

primary regulator of PTH secretion

Plasma Ca² + is the primary regulator ( inhibits ) Plasma Ca² + activates a calcium - sensing receptor ( CaSR ) in the membrane of chief cells in parathyroid gland . CaSR is a GPCR -- > Gaq -- > PLC -- > IP3 -- > Ca² +

Synthesis of Insulin Proinsulin

Preprohormone/ coded for by a single gene on human chromosome 11/ stimulated when ß cells of the pancreatic islet are exposed to glucose

PTH Receptor

Receptor binds the PTH 1R receptor most abundant on kidney ( proximal and distal convoluted tubules ) and bone ( osteoblasts )

Other hormones affect bone

Sex steroid and Glucocorticoids

Parathyroid Hormone - Related Peptide ( PTHRP )

Similar actions as PTH , same receptor . Made in Lactating breast Squamous cell tumors of the lung , head , and neck ; renal and bladder carcinomas ; adenocarcinomas ; and lymphomas

Role of Vitamin D.

Stimulate Ca² + absorption from the intestine, Stimulate Ca² + absorption from the kidney, Regulate bone resorption and formation, Repress transcription of PTH

PTH ___________ the activity of la - hydroxylase .

Stimulates

RANK ligand _________ bone resorption

Stimulates

Hypercalcemia

Symptoms : confusion , polydypsia ( increased thirst ) , polyuria ( increased urination ) , constipation , nausea , vomiting demineralization Formation of kidney stones

How Sex steroid hormones effect bone

Testosterone and estradiol maintain bone mass .

glycogen synthesis

The process of making glycogen

NaPi function :

Transports sodium with phosphate molecules

Binding of ________ inhibits transcription of the PTH gene .

Vitamin - D / RXR

2.Humoral Hypercalcemia of Malignancy

a.tumors that secrete PTHrP b.usually only very advanced malignancies produce hypercalcemia

Hypercalcemia of Malignancy 1.Local osteolytic hypercalcemia

a.when malignancy invades bone , produces cytokines that stimulate osteoclasts to break down bone releasing calcium

How does insulin affect glycolysis?

activate pyruvate kinase and glucokinase to promote Glycolysis

Osteocytes

are derived from osteoblasts , transfer mineral from the interior to growth surfaces

gain of function mutations in CASR result in

autosomal dominant hypocalcemia ( OMIM )

Calcitriol ( 1,25- ( OH ) ₂D3 )

biologically active form of VitD .

Most calcium is located in

bone

What is the net effect of Continuous PTH secretion

bone resorption

PTH stimulates both bone ___________ and bone ____________

bone resorption and bone formation

What do you parafollicular cells(C cells) in the thyroid gland secrete

calcitonin

PTH storage and circulation

cleaved into 2 fragments N - terminal and C - terminal

Glycolysis

conversion of glucose to pyruvate ( can be used in citric acid cycle to produce energy in the form of ATP )

PTH stimulates osteoblasts _________ and osteoclasts __________

directly and indirectly

Actions of Vitamin D in the small intestine and kidney : calcium absorption

does not regulate passive pathway of Ca² + absorption ( paracellular ) enhances Ca² + absorption via transcellular pathway in duodenum stimulates transcription of Ca² + channels , Ca 2+ pumps , ATPase and Ca2 + binding proteins

PTH 1 Receptor ( PTH1R ) cell signaling

exhibits dual intracellular signaling ( Gas Gaq )

Gluconeogenesis

formation of glucose from the breakdown of pyruvate

mutation causes severe hypercalcemia

homozygous mutation

la - hydroxylase

hydroxylates Vitamin D2 smd D3 in the liver and kidney to make active forms

PTH Receptor cell signaling

ii.PTHIR exhibits dual intracellular signaling 1.Gas -- > AC -- > CAMP -- > PKA ( primary signaling pathway ) 2.Gaq -- > PLC -- > IP₂ / DAG -- > PKC increase plasma

mild hypercalcemia elevated

ii.heterozygous mutation ( autosomal dominant )

Net effects of PTH signaling cascades are to

increase plasma Ca² + ] and decrease plasma [ phosphate ]

Insulin promotes glycogen synthesis by

increasing activity of glycogen synthase and inhibits glycogenolysis by decreasing activity of glycogen phosphorylase

GLUT2 transporters are insulin

independent

v.Exercise

inhibi insulin releas

iv.a - adrenergic receptors

inhibit insulin releas

Intracellular Ca2 + __________ PTH synthesis and secretion

inhibits

Calcitonin effect

inhibits bone resorption/Minimal contribution to calcium regulation Important in fish for dealing with high [ Ca² + ] in sea water important in uterus for implantation of the conceptus

Glycogen phosphorylase is dephosphorylated due to

insulin signaling

Glycogen synthase is inactive dephosphorylated due to

insulin signaling

OPG ( osteoprotegerin ) =

member TNF receptor family/ secreted by osteoblasts and blocks binding of RANKL to RANK

C peptide

no known biological activity Secreted with insulin

heterozygous mutation ( autosomal dominant ) levels

normal PTH levels , but elevated serum Ca² + levels , reduced urine Ca² + levels

Vitamin D Receptor ( VDR )

nuclear receptor which heterodimerizes with the retinoic acid receptor/ binds D3 with much higher affinity than D2

Which bone cell type has PTH receptor

osteoblasts

Calcitonin

peptide hormone / Produced by parafollicular cells ( C cell ) of the thyroid gland in response to elevated [ Ca² + ] .

Parathyroid hormone

peptide hormone/ synthesized as a pre - prohormone/ circulates as free hormone

glycogenolysis

process of breaking glycogen down into glucose

Osteoblasts

promote bone formation .

How Glucocorticoids affect bone

promote bone resorption

Osteoclasts

promote bone resorption located on growth surfaces of bone

Oxyphil cells

release PTHrP (PTH-like factor)

Osteoclasts resorb bone which does what?

releasing Ca2 + and phosphate

Tumors producing PTHRP will result in..

severe hypercalcemia

Vitamin D

steroid hormone/ Can be synthesized from 7 - dehydrocholesterol in the skin - requires UV radiation ( Vitamin D3 )

iii.ß - adrenergic receptors

stimulate insulin releas

Effects of PTH on the Kidney

stimulates Ca² + reabsorption in the distal tubules exchanger, inhibits PO4³- reabsorption mainly in proximal tubules, activate a - hydroxylase to produce the active form of Vitamin D ( VitD )

Feeding

stimulates insulin release before ingestion

Actions of Vitamin D in the Small Intestine and Kidney : phosphate absorption

stimulates phosphate absorption Stimulates transcription of Na / phosphate ( NaPi ) cotransporter This is the rate - limiting step for delivery of phosphate into the circulation

RANKL is a member of the

tumor necrosis family