Receptors Functions and Signal Transduction- L4- L5

1. Receptors Functions and Signal Transduction- L4- L5 Faisal I. Mohammed, MD, PhD University of Jordan 1

2. Tyrosine Kinase Receptors: University of Jordan

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4. Receptors superfamilies: • Ionotropic receptors (ligand-gated channels) • Metabotropic receptors (G protein-coupled receptors) • Tyrosine Kinase Almost all neurotransmitters discovered so far have more than one kind of receptor -- called receptor subtypes. University of Jordan

5. Epinephrine Can Act Through Two 2nd Messenger Systems University of Jordan

6. Blood capillary Blood capillary Blood capillary Blood capillary Free hormone Free hormone Free hormone Free hormone Lipid-soluble hormone diffuses into cell Lipid-soluble hormone diffuses into cell Lipid-soluble hormone diffuses into cell Lipid-soluble hormone diffuses into cell 1 1 1 1 Transport protein Transport protein Transport protein Transport protein 2 2 2 Activated receptor-hormone complex alters gene expression Activated receptor-hormone complex alters gene expression Activated receptor-hormone complex alters gene expression Nucleus Nucleus Nucleus Receptor Receptor Receptor DNA DNA DNA Cytosol Cytosol Cytosol mRNA mRNA mRNA 3 3 Newly formed mRNA directs synthesis of specific proteins on ribosomes Newly formed mRNA directs synthesis of specific proteins on ribosomes Ribosome Ribosome New protein 4 New proteins alter cell's activity Target cell Target cell Target cell Target cell Lipid-soluble Hormones

7. Hormones That Bind to Nuclear Receptor Proteins • Lipophilic steroid and thyroid hormones are attached to plasma carrier proteins. • Hormones dissociate from carrier proteins to pass through lipid component of the target plasma membrane. • Receptors for the lipophilic hormones are known as nuclear hormone receptors.

8. Nuclear Hormone Receptors • Steroid receptors are located in cytoplasm and in the nucleus. • Function within cell to activate genetic transcription. • Messenger RNA directs synthesis of specific enzyme proteins that change metabolism. • Each nuclear hormone receptor has 2 regions: • A ligand (hormone)-binding domain. • DNA-binding domain. • Receptor must be activated by binding to hormone before binding to specific region of DNA called HRE (hormone responsive element). • Located adjacent to gene that will be transcribed. University of Jordan

9. Mechanisms of Steroid Hormone Action • Cytoplasmic receptor binds to steroid hormone. • Translocates to nucleus. • DNA-binding domain binds to specific HRE of the DNA. • Dimerization occurs. • Process of 2 receptor units coming together at the 2 half-sites. • Stimulates transcription of particular genes. University of Jordan

10. Blood capillary Blood capillary Blood capillary Blood capillary Blood capillary Blood capillary 1 1 1 1 1 1 Binding of hormone (first messenger) to its receptor activates G protein, which activates adenylate cyclase Binding of hormone (first messenger) to its receptor activates G protein, which activates adenylate cyclase Binding of hormone (first messenger) to its receptor activates G protein, which activates adenylate cyclase Binding of hormone (first messenger) to its receptor activates G protein, which activates adenylate cyclase Binding of hormone (first messenger) to its receptor activates G protein, which activates adenylate cyclase Binding of hormone (first messenger) to its receptor activates G protein, which activates adenylate cyclase Water-soluble hormone Water-soluble hormone Water-soluble hormone Water-soluble hormone Water-soluble hormone Water-soluble hormone Adenylate cyclase Adenylate cyclase Adenylate cyclase Adenylate cyclase Adenylate cyclase Adenylate cyclase Receptor Receptor Receptor Receptor Receptor Receptor Second messenger Second messenger Second messenger Second messenger Second messenger G protein G protein G protein G protein G protein G protein 2 2 2 2 2 ATP ATP ATP ATP ATP Activated adenylate cyclase converts ATP to cAMP Activated adenylate cyclase converts ATP to cAMP Activated adenylate cyclase converts ATP to cAMP Activated adenylate cyclase converts ATP to cAMP Activated adenylate cyclase converts ATP to cAMP cAMP cAMP cAMP cAMP cAMP 6 Phosphodiesterase inactivates cAMP Protein kinases Protein kinases Protein kinases Protein kinases 3 3 3 3 cAMP serves as a second messenger to activate protein kinases cAMP serves as a second messenger to activate protein kinases cAMP serves as a second messenger to activate protein kinases cAMP serves as a second messenger to activate protein kinases Activated protein kinases Activated protein kinases Activated protein kinases Activated protein kinases 4 4 4 Activated protein kinases phosphorylate cellular proteins Activated protein kinases phosphorylate cellular proteins Activated protein kinases phosphorylate cellular proteins Protein Protein Protein ATP ATP ATP ADP ADP ADP Protein— Protein— Protein— P P P 5 5 Millions of phosphorylated proteins cause reactions that produce physiological responses Millions of phosphorylated proteins cause reactions that produce physiological responses Target cell Target cell Target cell Target cell Target cell Target cell Water-soluble Hormones University of Jordan

11. Paraventricular Peptide consisting of 3 amino acids Stimulates secretion of TSH by thyrotropes; stimulates expression of genes for  and ß subunits of TSH thyrotropes; stimulates synthesis of PRL by lactotropes Arcuate Single chain of 10 amino acids Stimulates secretion of FSH and LH by gonadotropes Paraventricular Single chain of 41 amino acids Stimulates secretion of ACTH by corticotropes; stimulates expression of gene for POMC in corticotropes Stimulates secretion of GH by somatotropes; stimulates expression of gene for GH in somatotropes Arcuate Single chain of 44 amino acids Inhibits secretion of GH by somatotropes Anterior periventricular Single chain of 14 amino acids Dopamine Arcuate Inhibits biosynthesis and secretion of PRL by lactotropes Hypophysiotropic Hormones Predominant hypothalamic localization Hormone Structure Actions on Anterior Pituitary Thyrotropin-releasing hormone (TRH) Gonadotropin-releasing hormone (GnRH) Corticotropin-releasing hormone (CRH) Growth hormone-releasing hormone (GHRH) Growth hormone-inhibiting hormone (somatostatin) Prolactin-inhibiting hormone (PIH)

12. Mechanism of Thyroid Hormone Action • T4 passes into cytoplasm and is converted to T3. • Receptor proteins located in nucleus. • T3 binds to ligand-binding domain. • Other half-site is vitamin A derivative (9-cis-retinoic) acid. • DNA-binding domain can then bind to the half-site of the HRE. • Two partners can bind to the DNA to activate HRE. • Stimulate transcription of genes.

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14. Cyclic Monophasphate (cAMP) Second Messenger Mechanism University of Jordan

15. Cell Membrane Phospholipid Second Messenger System University of Jordan

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17. Tyrosine Kinase University of Jordan

18. Tyrosine Kinase • Insulin receptor consists of 2 units that dimerize when they bind with insulin. • Insulin binds to ligand–binding site on plasma membrane, activating enzymatic site in the cytoplasm. • Autophosphorylation occurs, increasing tyrosine kinase activity. • Activates signaling molecules. • Stimulate glycogen, fat and protein synthesis. • Stimulate insertion of GLUT-4 carrier proteins. University of Jordan

19. Tyrosine Kinase (continued) University of Jordan

20. The Insulin Receptor & Mechanisms of Insulin Action University of Jordan

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23. Protein Hormones –Mechanisms of Action Tyrosine Kinase Mechanism Guanylate Cyclase Mechanism Adenylyl Cyclase Mechanism Phospholipid Mechanism University of Jordan

24. Steroid & Thyroid Hormones - Mechanism of Action University of Jordan

25. Determinants of Free Hormone Receptor Binding Carrier-bound hormone Free Hormone Hormone receptor Endocrine cell Biological effects Hormone degradation University of Jordan

26. Correlation of Plasma Half-Life & Metabolic Clearance of Hormones with Degree of Protein Binding Protein binding (%) Plasma half-life Metabolic clearance (ml/minute) Hormone Thyroid Thyroxine Triiodothyronine Steroids Cortisol Testosterone Aldosterone Proteins Thyrotropin Insulin Antidiuretic hormone 99.97 99.7 94 89 15 little little little 6 days 1 day 100 min 85 min 25 min 50 min 8 min 8 min 0.7 18 140 860 1100 50 800 600 MCR = (mg/minute removed) / (mg/ml of plasma) = ml cleared/minute University of Jordan

27. Circulating Transport Proteins Principle Hormone Transported Transport Protein Specific Corticosteroid binding globulin (CBG, transcortin) Thyroxine binding globulin (TBG) Sex hormone-binding globulin (SHBG) Nonspecific Albumin Transthyretin (prealbumin) Cortisol, aldosterone Thyroxine, triiodothyronine Testosterone, estrogen Most steroids, thyroxine, triiodothyronine Thyroxine, some steroids University of Jordan

28. + + _ + Feedback Mechanisms Positive Feedback Negative Feedback Target cell Endocrine cell Target cell Endocrine cell Biological effects Biological effects University of Jordan

29. Steroid & Thyroid Hormones - Receptors University of Jordan

30. Actions of Thyroid Hormones University of Jordan

31. Insulin Action on Cells: University of Jordan

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37. Signaling molecule (hormones) Receptor of target cell Signal transduction Intracellular molecule (second messengers) biological effect University of Jordan

38. Third messengers: Third messengers are the molecules which transmit message from outside to inside of nucleous or from inside to outside of nucleous, also called DNA binding protein. University of Jordan

39. Proteins and peptides: Hormones, cytokines Effect by membrane receptors Amino acid derivatives: Catecholamines Fatty acid derivatives: Extracellular molecules Prostaglandins Effect by intracellular receptors Signal molecules Steroid hormones, Thyroxine, VD3 Intracellular molecules cAMP, cGMP, IP3, DG, Ca2+ University of Jordan

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