ASCI 442 Unit 2 Notes

Thyroid, Parathyroid

TRH

thyrotropin releasing hormone

from the hypothalamus

7TM Gs or Gq 

TSH

thyrotropin stimulating protein

from the anterior pituitary

7TM Gs

thyromegaly

enlarged thyroid, increased TSH, decreased T3 and T4

thyroid gland/hormone effects

cellular differentiation and development

metabolic pathways

synthesis and release of TSH

stored in secretory granules

carbohydrate added in golgi

release regulated by H

lesions in median eminence block release

stimulation of preoptic area causes release

estrogen stimulates release

SST and T3/T4 inhibit

TSH, LH, FSH, and hCG have same alpha subunit and distinct beta subunit

secondary responses of TSH

increase cellular uptake of iodine

synthesize thyroglobulin, iodotyrosine, iodothyrosines

proteolysis of thyroglobulin

thyroid gland

TSH receptors - estrogen stimulates synthesis of the receptor, T3 and T4 inhibit receptor synthesis

function unit → follicle → secretory cells

C cells - parafollicular cells secrete calcitonin

calcium homeostasis

Goiter

enlarged thyroid, case for iodized salt

T3 and T4 made from

2 tyrosine (from thyroglobulin)

3 or 4 iodine

thyroglobulin 

allows for storage of hormones for up to 2 months

tyrosine coupling

Na+/I- symporter brings iodine into cell

Na+/K+ ATPase pump maintains Na+ gradient (out→in)

iodine must be at higher ocidative state for coupling, oxidized by thyroid peroxidase (PTO) H2O2 system, glucose regulation for NADPH production

endocytosis upon TSH → clipped off thyroglobulin → free T3/T4 secreted into the blood

excess iodine

iodoaldehydes with in the thyroid

Wolff-Chaikoff effect

impairs TPO leading to decreased T3 and T4 transient (1-2 d)

T3/T4 transport

serum levels: T4 70x > T3

half life: T4 - 7d; T3 - 1d

99% bound to proteins in circulation 

• thyroxine binding globulin

• albumen (lower affinity)

diffuse through membranes

free hormone carrient into cell via carrier proteins (MCT8)

nuclear receptor → ligand modulated transcription factor

T3 receptor in liver and kidney

binding highly correlated with synthesis of GH (synergistic effects)

Thyroid hormone regulation of differentiation and growth

brain, cartilage, lungs, regulation of GH and PRL

metabolism: O2 consumption, mineral balance, CHO/lipid/protein metabolism

cardiovascular - heart rate and output

hepatic synthesis of vitamin A

increased intestinal glucose absorption

hypothyroidism

deficiency of synthesis and secretion of thyroid hormones

cause

• absence of thyroid gland

• pathological destruction of thyroid gland

• insufficient secretion of thyroid hormones - elevated TSH

compensatory goiter: weakness, dry/coarse skin, lethargy, edema, cold, infertility, constipation, weight gain, impaired memory

Hashimoto’s Thyroiditis

autoimmune attack of the thyroid gland

increased TSH

10x more common in women

Hyperthyroidism

toxic goiter (Grave’s disease): autoimmune attack of thyroid gland, enlarged eyes

increased basal metabolic rate, cardiac output, temp, food intake, GI activity, diarrhea → weight loss

T3 and T4 biosynthesis

iodine transport

oxidation → Tyr

coupling

storage (colloid 2 mo)

endocytosis (induced by TSH binging to 7TM Gs) 

lysis

released into circulation

mechanism of action of T3 receptor

nuclear receptor

binds to TRE sequence of DNA

homo- or hetero-dimer

different forms of TR expressed through development

Thyroid hormone receptors

TRa1 - binds T3, DNA binding, heterodimer formation

TRa2 - does not bind T3, DNA binding, weak heterodimer formation

TRB1 - binds T3, DNA binding, heterodimer formation

TRB2 - binds T3, DNA binding, heterodimer formation

NO T3 = co-repressor (CoR) inhibits transcription

T3 binding = activation of transcription

Grave’s disease

fatigue, restlessness, tachycardia, weight loss despite eating, GI issues, increased temp

TSH low, thyroid enlarged

autoimmune - antibodies stimulate TSH receptor

hyperthyroidism

treat with antagonist for TSH receptor or T3 receptor

Calcium importance

muscle contraction, neurotransmission, cell signaling, skeletal support, coagulation enzyme and hormone regulation, exocytosis (secretion of hormones), mitosis

Ca and P

two most abundant elements

Ca transport

Ca typically bound

sequestered in mitochondria and ER

movement across membranes via channels and ATPase pumps

Calcium binding proteins

Troponin C - striated muscle

Parvalbumin - muscle

S-100 protein - nervous system, melanocytes

Vitamin D-dependent CaBP - cartilage, bone, teeth

Vitamin K-dependent CaBP - osteoblasts

Calmodulin - ubiquitous binding protein in all animals and plants

Ca regulated by

parathyroid - releases PTH in low Ca levels

kidney - regulates excretion of Ca and vitamin D

bone - bone mineralization, major source of Ca

PTH axis

parathyroid Ca receptor (CaSR)

7TMGPCR (Gi)

activation of PLC system through binding of Ca to CaSR to inhibit transcription of gene for PTH

low/no Ca → inhibition removed and PTH genes transcribes

parathyroid hormone (PTH)

produced and secreted by parathyroid gland

synthesized in pre-pro form → 84 aa

regulated by changes in [Ca] 

decreased Ca → increased PTH synthesis/secretion

secretion - fusion of secretory granule and exocytosis

parathyroid hormone related protein (PTHrP)

similar structure to PTH

works in similar manner, back up, in multiple tissues, 7TMGPCR

PTH mechanism to increase Ca

increased PTH → osteoblasts → produce RANKL → activate osteoclasts → breakdown bone

calcitonin

thyroid C-cells produce

inhibit action of osteoclasts and pre osteoblasts→osteoclasts

small effect compared to PTH

RANKL binding

estradiol and OPG (binding protein) - bind RANK L

estradiol protects bone by making OPG

PTH-R 

7TMGPCR (Gs & Gq) 

cause production of RANKL by osteoblasts, make pre osteoclasts from precursor cell

PTH action

direct in bone and kidney

bone - osteoblasts → RANKL → maturation of osteoclasts

kidney - formation of avtive vitamin D, increase Ca reabsorption, increased PO4 excretion

indirect: SI via vitamin D → increases Ca absorption

Bone cells

osteoblasts - build up bone

osteoclasts - break down bone

PTH on kidneys

cAMP

Ca reabsorption in distal tubules

increased PO4 excretion - proximal tubule, don’t want PO4 to increase with Ca

increased activity of a1-hydroxylase to form active vitamin D (1,25(OH)2D3)

Calcitonin

Gs

secreted by thyroid C-cells/parafollicular cells

protein with extreme PTM

regulation of secretion

• slight increase in Ca → increase in calcitonin secretion

• gastrin, secretin, cholecystokinin and glucagon stimulate release (anticipatory)

  • SST inhibits calcitonin

calcitonin in bone

inhibits resorption of Ca by osteoclasts

may not affect bone formation but protects bone mass

calcitonin in renal cortex

renal tubules have receptors

increase urinary excretion of Ca, PO4, Na, K

actions of vitamin D

increased Ca reabsorbtion in gut

bone formation and resorption

Ca reabsorption in kidney

intestine: increase permeability of SI to Ca

bone: mobilization of Ca

kidney: increased reabsorption of P and possibly Ca

muscle: increased muscle tone and contraction through Ca flux

DBP - binding protein

cholecalciferol → hydroxylated in liver and kidney → calcitriol (active)