Wednesday, March 14, 2012

Neuroendocrine Regulation of Thyroid Function I

1Basics¶

1.1Anatomy of the thyroid Gland¶

• weight about 15g
• left and right lobes are connected by isthmus
• congential hypothyroism: sometimes due to thyroid remains attach to tongue.

1.2Thyroid Hormones¶

• general structure: 2 benzene rings linked by ester bond. paraposition of outer ring is a hydroxyl group and paraposition of the inner ring is a alanine group.
• iodine at 5 position (C5 at inner ring) is vital for biological activity of thyroid hormone.
• $T_4$: 3,5,3'5' tetraiodothyronine , thyroxine : has four iodine, two on each rings
• $T_3$: 3,5,3' triodothyronine
• reverse $T_3$: doesn't have iodine at C5, so inactive. synthesized at hyperthyroism?

1.2.1Production¶

• produced in thyrocyte and stored in follicles
• Follicles have cavities surrounded by epithelial cells.
• that cavities are filled w/ colloids which are made of thyroglobulin
• thyroglobulin (Tg) are 330000 MW glycoprotein as a large monomer
• Tg also exist as dimer and polymerse, but dimers are more important.
• though huge, not particular rich in tyrosine.
• It's the spacial distribution of thyrosines creates hormonogenic sites (i.e sites of production).
  -- tyrosine residue (MIT and DIT) are spatially very close to each other
  -- this allow thyroid peroxidase, in presence of $H_2O_2$, to bring the coupling (oxidation )of the 2 thyroxine residues together.

1.2.2Biosynthesis and Secretion (Production in more details)¶

• On the basal surface of a thyroid cell there's NIS, a I-/Na+ symporter
  -- it concentrates I against gradient, energy comes from Na/K ATPase, pumping Na+ in drags I- in.
  -- I- in side the cell is 200 times that outside the cell
• I- is toxic so it's oxydized to $I_2$
• $I_2$ is incorporated into Tg, whose post translational modificatino includes glycosylation, dimerization, etc, before being dumped into the colloid.
  --$I^-$ can also be dumped into the colloid via pendrin, a tranporter at the apical surface
• thyroid synthesis: Tg is endocytosed by the cell and broken down by lysosome:
  -- $T_4$ and $T_3$ are released in the cells and send to the extracellular compartment
  -- MIT and DIT are recycled by enzymes which remove iodine from them.
• btw, MIT + DIT = 1 $T_3$ and 2 X DIT = 1 $T_4$
• also, Tg is a large reservoir, storing I and thyroid hormones and is effective for 4~ 6 weeks
  -- durgs that given to reduce hyperthyrodism don't take effect until after 4-6 weeks.

1.3Roles of Thyroid Hormones¶

• Growth and development and some specific functions in all vertebrae.
• For homeothermic species (warm-blooded animals): thermogenesis and ancillary metabolic effects
• Hormonal effects depend on the concentration in or around the cells
  -- Increase in plasma concentration also increases effect.

2Hypothalamic Pituitary Thyroid Axis¶

• In short: TRH (hypothalamus) --> TSH (anterior pituitary) --> $T_4$ and $T_3$ (thyroid)
• Paraventircular nucleus secretes TRH which induces secretion of TSH in the anterior pituitary.
• Thyrotropes in anterior pituitary produces TSH which induces thyroid secretion in the thyroid.
• $T_4$ and $T_3$ negative feedback onto production of TRH and TSH on hypothalamus and ant. pituitary, respectively.
  -- on TSH synthesis, processing (post-translational event) , etc

2.1Thyrotropin/Thyroid Stimulating Hormone (TSH)¶

• Normally $T_4$ and $T_3$ are high in plasma which correspond to low TSH. (physiological concentration)
• high TSH happens when there's hypothyroism.
• thyrotropes have a much greater secretory capacity than we normally observed.
• produced in ant. pituitary by basophilic cells (thyrotropes)

2.1.1Structure¶

• a glycoprotein, just like FSH, LH, and CG.
• subunits:
  -- alpha unit: common to all those 4 glycoproteins
  -- beta : different for each glycoproteins. site of receptor recognition. also the target of immuno essay.\ -- CHO moitie (carbohydrate) is important for biological activity and half life (makes the half life shorter)
• signaling:
  -- Gs: adenyl cyclase, PKA (major)
  -- Gq/11: phospholipase C, PKC (minor
  -- Cross-talking between signaling pathways.
• bovine TSH's two oligosaccharides are both sulfated
• In human, TSH has two different oligosaccharde chains: sulfated (SO4) and NeuAc
  -- rhTSH: a recombinant human TSH, both chains are NeuAc --> prolong the halfh life so enlongate biological activity.

2.1.2Circadian rhythm¶

• Pulsatile
• high at night and early in the morning
• no difference between men and women
• However, older women display more robust TSH secretion than younger women.
  -- Doesn't happen in men.
• What makes the diural pattern? Experiment in rodents show:
  -- corticosterone has no effect on TSH's rhythm.
  -- ablation of suprachiasmatic nucleus (site of biological clock) abolishes the rhythm.
  -- so SON is responsible for TSh's circadian pattern. but it's also due to differnetial expression of Type 2 DIOD-2 (will be discussed later)

2.1.3Effects on the thyroid glands¶

• Earliest effect is on the released of thyroid hormones (ready-made) by stimulating
  --Tg endocytosis
  --Digestion and release of iodoaminoacids
  -- intrathyroidal deiodination of iodotyrosines (MIT and DIT)
• stimulate synthesis of thyroid hormones
  -- NIS (the transporter) level and activity
  -- I- oxidation and organification
  -- Coupling of iodotyrosines (MIT and DIT)
  -- Tg synthesis and processing
  -- Deiodination (by D1)
• thyroid cell replication and differentiation
  -- therefore it's responsible for goiter (enlargement of thyroid)
• It however does NOT increase expression/activity of pendrin (that transporter on the apical surface）

2.2TRH (thyrotropin releasing hormone)¶

• TSH structure: three amino acid neuropeptide ! (pyroglutamyl-histidyl-prolinamide .. )

2.2.1Hypothalamic pituitary connections¶

• TRH is released from paraventircular (PVN) and arcuate (ARC) nuclei and transport via infundibulum (stalk that connects hypothalamus and ant. pituitary) to reach thyrotropes.
  -- PVN is superior to ARC, which is right above the median eminence. All three are at the level of third ventricle.
  -- Not all cells in PVN makes TRH. Only those that line the third ventricle do.
• pituitary gland rests in sella turcia, a saddle-shaped depression in the sphenoid bone. the stalk is outside of sella turcia
  -- post. pituitary receives arterial blood but ant. pituitary receives venous blood from venux plexus in the stalk (infundibulum)
  -- basically for ant pituitary: arterial blood --> super hypophyseal artery --> venous plexus at the level of the stalk (where hormones from hypothalamus are dumped into) --> secondary venous plexus in ant. pituitary --> hormones in the venous blood act on ant. pituitary --> ant. pituitary secrete its hormones and dump them into the portal blood.
• innervation of TRH neurons in PVN
  -- C1/A1 nuclei project onto PVN nucleus and secrete norepinephrine and epinephrine upon cold exposure
  -- ARC secrete neuropeptins onto PVN on appetite control: Orexigenic (NPY and AGRP) and anorexogenic (MSH , CART)

2.2.2Effects of TRH on TSH-producing cells¶

• stimulates secretion of TSH, synthesis of new TSH
• glycosylation of TSH at post-translational stage
  -- if TRh is blocked from reaching TSH producing cells --> hypothyroisim (low T3 and T4) because TSH has very little biological activity when it's w/o the carbohydrate moitie.
• There are tons of non-hypophysiotropic effects of TRH/TRH derived peptides but you don't need to memorize them unless you want to.

2.2.3TRH, TSH, thyroid hormone interactions in thyrotrophs###¶

• T3 can suppress TRH at level of hypothalamus, TSH gene and mRNA translation at ant. pituitary gland and post translational events of TSH.
• TRH upregulate TSH in thyrotroph.
  -- Action via transcription factors: CBP and Pit1, which act on transcription of the beta subunit specific for TSH
  -- Pit 1 is also important for prolactin and growth hormone expression.
• TSH's pulses:
  -- stimulatory: TRH and AVP (vasopressin)
  -- 2 inhibitory: dopamine and somatostatin

3T3 and T4#¶

3.1Production##¶

• Most T3 in human is made outside of the thyroid
  -- T4 is made exclusively in thyroid
  -- 20% T3 comes from thyroid, 80% comes from T4 being converted into T3 by D2 and D1 in the periphery.
• T4 ---(D2,D1)--> 5' deiodination --> T3 ---(D3, D1) --> 5-deionization -->T2 (inactive)
• T4 ---(D3,D1)--> 5 deiodination --> reverse T3 ---(D2, D1) --> 5'-deionization -->T2 (inactive)

3.2Functions¶

• T3 is 10X more potent, stronger in affinity, and more abundant than T4.
  -- so T3 is ultimately responsible for most of the thyroid hormone activity
  -- since most T3 comes from T4, T4 can be seen as T3 prohormone

• in liver and kidney, 40% of receptor is occupied and most of them are by T3 from thyroid.

• In ant. pituitary, 90% receptor is occupied
  -- strong negative feedback on TSH secretion --> euthyroid (i.e. normal thyroid) TSH secretion (minimal fraction of maximal secretion potential)
  -- most T3 that bind to pituitary derives from T4 because pituitary likes converting T4 to T3, allowing it to modulate amount of T3 to bind to its receptors.
  -- There's very little T4 found in pituitary nuclei as most of them got converted to T3:
  -- T4 contributes a large fraction of the nuclear T3 in the TSH producing cells.

3.3Regulation##¶

• T4's importance for TSH regulation can be seen in hypothyroism.
  -- as individuals become more and more hypothyroid-y, T4 would fall while T3 is maintained relatively constant
  -- basically body tries to maintain the higher potency T3 in response to increase need of T3
  -- and ofc, TSH will greatly increase (because receptor occupancy at ant. pituitary falls
  -- as TSH goes up, thyroid produces more T3 (contrary to usually produce 20% of circulating T3) by upregulating D2/D1
• in situ hybridization shows cerebral T3 autoregulation
  -- in hypothyroism, D3 mRNA level is low in hippocampus. In hyperthyroism, it's very high.
  -- upregulation of D2 on surface of ventricle and ant. pituitary in hypothyroism --> an effort to maintain T3 level in the brain while circulating level is low
  -- Astrocyte: has OATP (organic anion transport protein) which pumps T4 from serum into the cell.
  --astrocyte has D2 , converting T4 to T3. It also has UPS (ubiquitin protein system) which can degrades D2 (in event of hyperthyroism)
  -- T3 then acts on astrocyte's nucleus or go into neuron via MCT8 (another transport protein)
  -- neuron either inactivate T3 by expressing D3 or T3 acts on nucleus to decrease D3 transcription.
  *There are other factors that act on hypothalamus in regulating thyroid hormone --> next class.