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Receptors Functions and Signal Transduction- L4- L5 Faisal I. Mohammed, MD, PhD University of Jordan 1 Tyrosine Kinase Receptors: University of Jordan 2 University of Jordan 3 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 4 Epinephrine Can Act Through Two 2nd Messenger Systems University of Jordan 5 Free hormone Blood capillary 1 Lipid-soluble Transport protein hormone diffuses into cell 2 Activated Nucleus Receptor receptor-hormone complex alters gene expression DNA Cytosol mRNA 3 Newly formed mRNA directs synthesis of specific proteins on ribosomes Ribosome New protein 4 New proteins alter Lipid-soluble Hormones cell's activity Target cell 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. 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 8 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 9 Blood capillary 1 Binding of hormone (first messenger) to its receptor activates G protein, which activates adenylate cyclase Water-soluble hormone Adenylate cyclase Receptor Second messenger G protein ATP cAMP 2 Activated adenylate cyclase converts ATP to cAMP Protein kinases 6 Phosphodiesterase inactivates cAMP 3 cAMP serves as a second messenger to activate protein kinases Activated protein kinases 4 Activated protein Protein kinases phosphorylate cellular proteins ATP ADP Water-soluble Hormones Protein— P 5 Millions of phosphorylated proteins cause reactions that produce physiological responses University of Jordan Target cell 10 Hypophysiotropic Hormones Hormone Predominant hypothalamic localization Structure Actions on Anterior Pituitary Thyrotropin-releasing hormone (TRH) Paraventricular Peptide consisting of Stimulates secretion of TSH by 3 amino acids thyrotropes; stimulates expression of genes for and ß subunits of TSH thyrotropes; stimulates synthesis of PRL by lactotropes Gonadotropin-releasing hormone (GnRH) Arcuate Single chain of 10 amino acids Stimulates secretion of FSH and LH by gonadotropes Corticotropin-releasing hormone (CRH) Paraventricular Single chain of 41 amino acids Stimulates secretion of ACTH by corticotropes; stimulates expression of gene for POMC in corticotropes Growth hormone-releasing hormone (GHRH) Arcuate Single chain of 44 amino acids Stimulates secretion of GH by somatotropes; stimulates expression of gene for GH in somatotropes Single chain of 14 amino acids Inhibits secretion of GH by somatotropes Dopamine Inhibits biosynthesis and secretion of PRL by lactotropes Growth hormone-inhibiting Anterior hormone (somatostatin) periventricular Prolactin-inhibiting hormone (PIH) Arcuate 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 halfsite of the HRE. Two partners can bind to the DNA to activate HRE. Stimulate transcription of genes. University of Jordan 13 Cyclic Monophasphate (cAMP) Second Messenger Mechanism University of Jordan 14 Cell Membrane Phospholipid Second Messenger System University of Jordan 15 University of Jordan 16 Tyrosine Kinase University of Jordan 17 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 18 Tyrosine Kinase (continued) University of Jordan 19 The Insulin Receptor & Mechanisms of Insulin Action University of Jordan 20 University of Jordan 21 University of Jordan 22 Protein Hormones – Mechanisms of Action Adenylyl Cyclase Mechanism ACTH LH FSH TSH GHRH Somatostatin ADH (V2 receptor) HCG MSH CRH Calcitonin PTH Glucagon Phospholipid Mechanism Guanylate Cyclase Mechanism GnRH TRH PTH Angiotensin II ADH (V1 receptor) Oxytocin ANP University of Jordan Tyrosine Kinase Mechanism Insulin IGF-1 GH Prolactin 23 Steroid & Thyroid Hormones - Mechanism of Action University of Jordan 24 Determinants of Free Hormone Receptor Binding Carrier-bound hormone Endocrine cell Free Hormone Hormone receptor Hormone degradation Biological effects University of Jordan 25 Correlation of Plasma Half-Life & Metabolic Clearance of Hormones with Degree of Protein Binding Hormone Protein Plasma half-life binding (%) Metabolic clearance (ml/minute) Thyroid Thyroxine Triiodothyronine 99.97 99.7 6 days 1 day Steroids Cortisol Testosterone Aldosterone 94 89 15 100 min 85 min 25 min 140 860 1100 Proteins Thyrotropin Insulin Antidiuretic hormone little little little 50 min 8 min 8 min 50 800 600 0.7 18 MCR = (mg/minute removed) / (mg/ml of plasma) = ml cleared/minute University of Jordan 26 Circulating Transport Proteins Principle Hormone Transported Transport Protein Specific Cortisol, aldosterone Corticosteroid binding globulin (CBG, transcortin) Thyroxine binding globulin (TBG) Thyroxine, triiodothyronine Testosterone, estrogen Sex hormone-binding globulin (SHBG) Nonspecific Albumin Transthyretin (prealbumin) University of Jordan Most steroids, thyroxine, triiodothyronine Thyroxine, some steroids 27 Feedback Mechanisms Positive Feedback Negative Feedback + + Endocrine cell _ Target cell Endocrine cell Target cell + Biological effects Biological effects University of Jordan 28 Steroid & Thyroid Hormones - Receptors University of Jordan 29 Actions of Thyroid Hormones University of Jordan 30 Insulin Action on Cells: University of Jordan 31 University of Jordan 32 University of Jordan 33 University of Jordan 34 University of Jordan 35 University of Jordan 36 Signaling molecule (hormones) Receptor of target cell Signal transduction Intracellular molecule (second messengers) biological effect University of Jordan 37 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 38 Effect by membrane receptors Extracellular molecules Effect by intracellular receptors Signal molecules Intracellular molecules Proteins and peptides: Hormones, cytokines Amino acid derivatives: Catecholamines Fatty acid derivatives: Prostaglandins Steroid hormones, Thyroxine, VD3 cAMP, cGMP, IP3, DG, Ca2+ University of Jordan 39 University of Jordan 40