Principles of metabolism regulation

1. Principles of metabolism regulation Molecular mechanisms of hormonal signal transduction

2. Ways of cell communicationAutocrine way of signal trunsduction Secretory cell is also a target for its own hormone • Secretorycellsecretes a hormone into extracellular medium. A hormone binds to the same cell inducing physiological response.

3. Ways of cell communicationParacrine way of signal trunsduction • There are several types of cells in an organ/tissue. • Secretory cells releasefirst messenger (hormone) into extracellular medium. First messenger can reach an adjacent cell and combine with its receptors Secretorycell

4. Target cell Secretory cell Receptor Blood Hormone Ways of cell communicationEndocine way of signal trunsduction • A cell secretes a chemical compound into blood. Blood transports this compound into tissues, where a compound combines with cells inducing physiological response.A chemical compound secreted into blood is first-messenger. In physiological terms, it is a hormone. • An organ (tissue) upon which a hormone acts is considered as a target-organ(tissue). • Cells of target organ/tissue contain receptors specific in regard to a hormone. Receptors =proteins.

5. Precursors Hypothalamus Statins Inhibitors Liberins, Activators Precursors Adenohypophysis Tropins Feedback inhibition Precursors Peripheral endocrine gland Hormone Ultimate target Response Neuroendocrine system and its ranking • Hypothalamic-hypophyseal axis is controled by neural imputs from CNS. • Hypothalamic hormones act on cells of adenohypophysis. Cells of adenohypophysis are considered as first rank target cells. • Hormones of adenohypophysisact on cells of peripheral endocrine glands. The cells of peripheral endocrine glands are second rank target cells. • Hormones of peripheral endocrine glands act on cells of various tissues. These cells are ultimate targets or third rank of target cells.

6. Feedback inhibition in neuroendocrine system

7. Receptors in plasma membrane Complex of receptor and hormone Receptors for calcitriol, thyroid hormones and retinoic acid Nucleus Plasma membrane Cytosole Steroid Receptor in cytosol Hypothetical model of target cell

8. Functional classification of plasma membrane reseptors • Receptorslinked to adenylate cyclase system. Cyclic adenosine monophosphate(cAMP) is second messenger. • Receptorslinked to phospholipase C system. Inositol triphosphate (IP3), diacylglycerol (DAG) ir Ca2+ are second messengers. • Receptors with enzymatic properties: receptory tyrosine kinase and receptory guanylate cyclase.

9. Hormone action via plasma membrane receptors • These receptors are characteristic to all hormones soluble in water. • The main steps of action: formation of H-R complex; synthesis of second messenger (second messenger is a regulatory molecule immediately produced in a target cell in response to hormone); alterations of activities of intracellular enzymes; physiological response.

10. ATP ADP ATP ADP Hormone Receptor Receptor Plasma membrane Functioning of receptors linked to adenylate cyclase Adenilatciklaz Adenylate cyclase ė G-protein - b a ltymas Proteinkinase A Proteinkinazė A Neaktyvi Inactive Proteinkinase A active i Phosphorylase kinase Inactive, dephosphorylated Phosphorylase kinase Active, phosphorylated Glycogenphosphorylase b inactive dephosphorylated Glycogenphosphorylase a ative Glycogen( n) cAMP-mediated breakdown of glycogen (Glucose-1-phosphate) n

11. Synthesis of cAMP Adenylate cyclase

12. cAMP decomposition Phosphodiesterase H2O Inhibited by alkaloids, e.g. caffeine

13. Hormones acting via cAMP • Glucagon • Adrenalin (activation β-adrenoreceptorsresults in cAMP increasing, butα2 –in increasing) • Calcitonin • Vasopressin (ADH, antidiuretic hormone) if interacts with V2-type receptors in cells of distal tubules of kidney.

14. G-proteins as mediators of R-enzyme interaction H H Adenylate cyclase

15. Hormone G-protein Receptor Phospholipase C Proteinkinase C Ca-calamodulin complex Secretory vesicles ER Transduction of hormonal signal through phospholipase C system

16. Hormones acting via phospholipase C system • Adrenalin/noradrenalin (viaα1-adrenoreceptors) • Vasopressin (ADH) via V1receptors (in smooth muscles cells of blood vessels)

17. Enzymatic receptors. Hormones acting via enzymatic receptors • Insulin • Somatotropin/ growth hormone (GH) • Insulin-like growth factors • Cytokins • Natriuretic peptides

18. Fibroblast growth factor receptor Epidermal growth factor receptor Insulin receptor Imunoglobuline domens Cys-domens Cys-domens Tirosinkinase Receptors with tyrosine kinase activity: receptory tyrosine kinase

19. Receptors with guanylate cyclase activity

20. Synthesis of cGMP by guanylate cyclase GTP cGMP

21. Action of hormones via intracellular receptors • Intracellular receptors bind only water insoluble hormones (lipophilic ones: steroid-, thyroid hormones and retinoic acid). • True second messengers are not produced. • Receptors are located in cytoplasm and nucleus of target cells.

22. Plasma membrane Hormone ir protein complexs Free hormone Nucleus ŠŠB Branduolio receptoriai Citozolio receptoriai Activation Activation Response Protein Hormone action through intracellular receptors Baltymas

23. Heat shock protein DNR binding site Hormone Hsp and receptor complex

24. Length varies Functional areas A/B E C DNA binding domain Hormone- binding domain Regulatory domain Nuclear targeting sequence E A/B D C Structure of receptor specific to lipophilic hormone