Endocrinology, lecture on the Thyroid Axis
USD Department of Biology
Endocrinology
Summers
Hormones
Endocrine Glands
Receptors
Homeostasis
2nd Messengers
Nuclear Receptors
Genetic Regulation
Hormone Synthesis
Receptor Regulation
Hypothalamo-Hypophysial Communication
Tropic Hormones
Neurohypophysial Nonapeptides
Thyroid Axis
Steroids
Adrenal Axis
Adrenal Medulla
Osmotic-Pressure Balance
Reproductive Endocrinology
Prolactin
Somatic Axis
Growth Factors
Immune Factors
Ca++, PO4 Homeostasis
Pancreatic Hormones
GI Hormones
Guts 'n Brains
Brain Hormones
Neurosteroids
Neuropeptides
Endocrine Evolution
Figures for Endocrionology
text:Vertebrate Endocrinology5th Edition - David O. Norris:
Read pages 207-229 for this lecture
acronyms    end
XIII. Thyroid Axis 			


	A. Hypothalamo-Hypophysial-Thyroid Cascade
	

		1. TRH stimulates TSH


		2. TSH stimulates T4


			a. and T3


		3. T4 converted into T3 at tissues 


			a. carrier protein


		4. T3 binds to nuclear receptor


			a. present in all tissues


				i. including hypothalamus and pituitary - feedback


		5. T3 predominantly responsible for negative feedback


	B. TRH


		1. 3 aa		(pyroGlu-His-Pro-NH2)								
					pyroGlu = N-terminal glutamic acid closed into a lactam ring

			a. preprohormone = 255 aa


				i. 5 TRH molecules


				ii. locations of the TRH sequences are conserved
				     between amphibian and mammalian


			b. produced in the PVN, PVa, AH, POA, DMN, VMN and ARC
			   of the hypothalamus


				i. primarily  PVN and PVa


				ii. stimulated by cold,  inhibited by stress


					(1) stimulated by NE, Epi, H (histamine)
					     and maybe ACh


					(2) inhibited by GABA, DA, enkephalins, 5-HT
					    (of course negative feedback)


		2. TRH stimulates TSH


			a. TSH inhibited by somatostatin


		3. TRH stimulates PrL


		4. one receptor


			a. TRH-R up-regulated by estrogen


			b. down-regulated by thyroid hormones


			c. 2nd messengers: IP3, Ca++, PKC, cAMP
			
			
				i. IP3/Ca++/PKC & cAMP
				    are involved in TSH & PrL release
					
					
					(1) Ca++ is always involved
					     in endocytosis/release


	C. TSH


		1. 10% of all cells of the pars distalis


			a. smallest cells of pars distalis


		2. a subunit = 92 aa (also LH, FSH, CG)


			a. single a-subunit gene for all glycoprotein hormones


				i. 4 exons and 3 introns						


				ii. mRNA codes for 116 aa
				     - 24 aa signal peptide (N-terminal end)


		3. b = 112 aa


			a. gene is on different chromosome from gene for a-subunit 


		4. half-life = 60 min


			a. inactivated in liver and kidney


		5. Function = production and release of thyroid hormones


			a. thyroid hormones are also regulated by stimulation from the
			    sympathetic nervous system and other nerves containing VIP


			b. hypertrophy and vascularization of thyroid



			c.  cAMP


				i.  uptake of iodide


				ii.  synthesis of thyroglobulin,
				     iodo- tyrosine and thyronines


				iii. pinocytosis of thyroglobulin


				iv. proteolysis of thyroglobulin
				     and release of T3 and T4


			d. lipolytic


		6. one receptor type on thyroid cells and adipocytes


			a. high affinity, low capacity


			b. 2 subunits


	D. Thyroid


		1. anterior portion of the neck					


		2. Follicle = functional unit						


			a. sphere of a single layer of cuboidal cells	
			

				i. surrounding the colloid


					(1) made up of thyroglobin
					   - an iodinated glycoprotein


				ii. height of follicular cells increases
				     with glandular stimulation


				iii. classical secretory cells with well 
				      developed rER and Golgi apparatus


			b. microvilli of the apical plasma membrane extend 
			    into the follicular lumen = pseudopods


		3. thyroid also contains larger epithelial 
		   clear or C cells which secrete calcitonin


	E. Thyroid Hormones


		1. Iodination


			a. thyroid hormones are iodinated amino acids


			b. while in the thyroid they are a part of the peptide
			   chain of thyroglobulin = 669kd


			c. thyroid concentrates dietary iodide


				i. iodide pump


			d. tyrosine residues bind (up to two) oxidized iodines 						


				i. oxidized by thyroid peroxidase


			e. iodotyrosine residues couple to make iodothyronine


			f. proteolysis releases free hormone


		2. Thyroxine = T4 , 3,5,3'-Tri-iodothyronine = T3


			a. half-life = 7 and 1 day respectively



		3. Storage and Release							


			a. non-iodinated thyroglobulin is transferred to
			   (exocytosis) & stored in the lumen of the follicle


				i. iodinated at the apical membrane		


				ii. not directly active and away from metabolic processes


			b. thyroglobulin repenetrates the cell by pinocytosis


			c. endocytotic vesicles fuse with lysosomes
			    containing proteolytic enzymes


			d. proteolysis produces T3, T4,
			    MIT (monoiodinated tyrosine), and DIT


			e. T3 and T4 are released
			    tyrosines and iodide recycled


			f. carried in the blood by thyroid binding proteins

			
		4. T3 Receptors


			a. nuclear receptor superfamily (2 immediate-early genes)


				i. tissue specific differences


					(1) T3-Rb1 is everywhere,
					     T3-Rb2  in pituitary and CNS


						(a) gene for T-Rb on  chromosome 3


					(2) T3-Ra1 in skeletal muscle and  brown fat,
					     T-Ra2 doesn't bind T3 (may be inhibitory)


						(a) gene for T-Ra on  chromosome 17


				ii. ~45,000 d


			b. binds T3     (KD ~10-10 M = 0.1nM)


				i. also T4, but with 10X lower affinity


					(1) T4 converted to T3 intracellularly


			c. induces gene transcription / mRNA synthesis
			
			
		5. Function


			a. receptors and function in almost all tissue


			b. Development


				i. differentiation and maturation of fetal tissue


					(1) especially nervous and bone tissue


					(2) lung surfactant


				ii. growth


					(1)  GH production and effectiveness


				iii. stimulates amphibian metamorphosis


			c. Metabolism


				i.  metabolism of proteins, sugars, lipids,
				    H2O, N, and O2


				ii. synergism with insulin, steroids, catecholamines


				iii. heat production

XIV. Steroids

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