Principles of metabolism regulation Molecular mechanisms of hormonal signal transduction

Secretory cell secretes a hormone into extracellular medium. A hormone binds to the same cell inducing physiological response. Secretory cell is also a target for its own hormone Ways of cell communication Autocrine way of signal trunsduction

There are several types of cells in an organ/tissue. Secretory cells release first messenger (hormone) into extracellular medium. First messenger can reach an adjacent cell and combine with its receptors Ways of cell communication Paracrine way of signal trunsduction Secretory cell

Ways of cell communication Endocine 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. Secretory cell Target cell Blood Hormone Receptor

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 adenohypophysis act 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. Neuroendocrine system and its ranking Precursors Hypothalamus Liberins, Activators Statins Inhibitors Adenohypophysis Feedback inhibition Tropins Peripheral endocrine gland Hormone Ultimate target Response

Feedback inhibition in neuroendocrine system

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

Functional classification of plasma membrane reseptors Receptors linked to adenylate cyclase system. Cyclic adenosine monophosphate (cAMP) is second messenger. Receptors linked to phospholipase C system. Inositol triphosphate (IP 3 ), diacylglycerol (DAG) ir Ca 2+ are second messengers. Receptors with enzymatic properties: receptory tyrosine kinase and receptory guanylate cyclase.

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.

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

Synthesis of cAMP Adenylate cyclase

cAMP decomposition Phosphodiesterase H2OH2O Inhibited by alkaloids, e.g. caffeine

Hormones acting via cAMP Glucagon Adrenalin (activation β-adrenoreceptors results in cAMP increasing, but α2 –in increasing) Calcitonin Vasopressin (ADH, antidiuretic hormone) if interacts with V2-type receptors in cells of distal tubules of kidney.

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

Transduction of hormonal signal through phospholipase C system Hormone Receptor G-protein Phospholipase CProteinkinase C ERER Ca-calamodulin complex Secretory vesicles

Hormones acting via phospholipase C system Adrenalin/noradrenalin (via α 1- adrenoreceptors) Vasopressin (ADH) via V 1 receptors (in smooth muscles cells of blood vessels)

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

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

Receptors with guanylate cyclase activity

Synthesis of cGMP by guanylate cyclase GTP cGMP

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.

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

Hsp and receptor complex Heat shock protein DNR binding site Hormone

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