Receptors Functions and Signal Transduction- L4- L5
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1 Receptors Functions and Signal Transduction- L4- L5 Faisal I. Mohammed, MD, PhD University of Jordan 1
2 PKC Phosphorylates many substrates, can activate kinase pathway, gene regulation PLC- signaling pathway
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 3
4 Blood capillary Water-soluble hormone Receptor 1 Binding of hormone (first messenger) to its receptor activates G protein, which activates adenylate cyclase Adenylate cyclase G protein ATP Protein kinases camp Second messenger 2 3 camp serves as a Activated second messenger protein to activate protein kinases kinases Protein ATP 6 Activated adenylate cyclase converts ATP to camp 4 Phosphodiesterase inactivates camp Activated protein kinases phosphorylate cellular proteins Water-soluble Hormones ADP Protein P 5 Millions of phosphorylated proteins cause reactions that produce physiological responses University of Jordan 4 Target cell
5 University of Jordan 5
6 Cyclic Monophasphate (camp) Second Messenger Mechanism University of Jordan 6
7 Cell Membrane Phospholipid Second Messenger System University of Jordan 7
8 Epinephrine Can Act Through Two 2 nd Messenger Systems University of Jordan 8
9 Free hormone Blood capillary Transport protein 1 Lipid-soluble hormone diffuses into cell 2 3 Activated receptor-hormone complex alters gene expression Cytosol Newly formed mrna directs synthesis of specific proteins on ribosomes Nucleus Receptor DNA mrna Ribosome New protein Lipid-soluble Hormones 4 New proteins alter cell's activity Target cell
10 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.
11 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 11
12 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 12
13 Mechanism of Thyroid Hormone Action T 4 passes into cytoplasm and is converted to T 3. Receptor proteins located in nucleus. T 3 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.
14 Steroid & Thyroid Hormones - Mechanism of Action University of Jordan 14
15 Actions of Thyroid Hormones University of Jordan 15
16 Determinants of Free Hormone Receptor Binding Carrier-bound hormone Endocrine cell Free Hormone Hormone receptor Hormone degradation Biological effects University of Jordan 16
17 Correlation of Plasma Half-Life & Metabolic Clearance of Hormones with Degree of Protein Binding Hormone Thyroid Thyroxine Triiodothyronine Steroids Cortisol Testosterone Aldosterone Proteins Thyrotropin Insulin Antidiuretic hormone Protein binding (%) little little little Plasma half-life 6 days 1 day 100 min 85 min 25 min 50 min 8 min 8 min Metabolic clearance (ml/minute) University of Jordan 17
18 Circulating Transport Proteins Transport Protein Specific Corticosteroid binding globulin (CBG, transcortin) Thyroxine binding globulin (TBG) Sex hormone-binding globulin (SHBG) Nonspecific Albumin Transthyretin (prealbumin) Principle Hormone Transported Cortisol, aldosterone Thyroxine, triiodothyronine Testosterone, estrogen Most steroids, thyroxine, triiodothyronine Thyroxine, some steroids University of Jordan 18
19 Feedback Mechanisms Negative Feedback Positive Feedback + + Endocrine cell _ Target cell Endocrine cell + Target cell Biological effects Biological effects University of Jordan 19
20 Steroid & Thyroid Hormones - Receptors University of Jordan 20
21 Enzyme-linked Receptor (the Leptin receptor) JAK= Janus Kinase STAT= Signal Transducer and Activator of Transcription
22 Tyrosine Kinase University of Jordan 22
23 Tyrosine Kinase Receptors: University of Jordan 23
24 University of Jordan 24
25 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 25
26 Tyrosine Kinase (continued) University of Jordan 26
27 The Insulin Receptor & Mechanisms of Insulin Action University of Jordan 27
28 University of Jordan 28
29 Insulin Action on Cells: University of Jordan 29
30 University of Jordan 30
31 University of Jordan 31
32 University of Jordan 32
33 University of Jordan 33
34 University of Jordan 34
35 Signaling molecule (hormones) Receptor of target cell Intracellular molecule (second messengers) Signal transduction biological effect University of Jordan 35
36 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 36
37 Extracellular molecules Effect by membrane receptors Proteins and peptides: Hormones, cytokines Amino acid derivatives: Catecholamines Fatty acid derivatives: Prostaglandins Signal molecules Effect by intracellular receptors Steroid hormones, Thyroxine, VD 3 Intracellular molecules camp, cgmp, IP 3, DG, Ca 2+ University of Jordan 37
38 University of Jordan 38
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