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 communicationAutocrine 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 communicationParacrine way of signal trunsduction

Secretory cell

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.

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

Precursors

Precursors

Hypothalamus

Liberins,Activators

StatinsInhibitors

Adenohypophysis

Feedback inhibitionTropins

Peripheralendocrinegland

Hormone

Ultimate target

Response

Feedback inhibition in neuroendocrine system

Hypothetical model of target cellReceptors in plasma membrane

Complex of receptor and hormone

Nucleus

Plasma membrane

Cytosole

Receptors for calcitriol,thyroid hormonesand retinoic acid

Steroid

Receptor in cytosol

Functional classification of plasma membrane

reseptorsReceptors linked to adenylate cyclase system. Cyclic adenosine monophosphate (cAMP) is second messenger.Receptors linked 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.

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

InactiveProteinkinase AactivePhosphorylase kinase

Inactive, dephosphorylatedPhosphorylase kinaseActive, phosphorylated

ATP ADP

Glycogenphosphorylase binactive dephosphorylated

Glycogenphosphorylase aative 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

H2O

Inhibited by alkaloids, e.g. caffeine

Hormones acting via cAMPGlucagonAdrenalin (activation β-adrenoreceptors results in cAMP increasing, but α2 –in increasing)CalcitoninVasopressin (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

HormoneReceptor G-protein

Phospholipase C Proteinkinase C

ER

Ca-calamodulincomplex

Secretoryvesicles

Hormones acting via phospholipase C system

Adrenalin/noradrenalin (via α1-

adrenoreceptors)Vasopressin (ADH) via V1receptors (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 kinaseEpidermal growth factorreceptor

Fibroblast growthfactor receptor

Cys

-dom

ens

Insulin receptor

Cys

-dom

ens

Imun

oglo

buli

ne d

omen

s

Tirosinkinase

Guanylate cyclase

NUP

Guanylate cyclase

Guanylate cyclase

Guanylate cyclase

NUP

Guanylate cyclase

Guanylate cyclase

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 irprotein complexs

Free hormone Plasma membrane

Nucleus

Branduolioreceptoriai

Citozolioreceptoriai

ŠŠB

ProteinResponse

Activation

Activation

Hsp and receptor complexHeat shock protein

DNR binding site

Hormone

Structure of receptor specific to lipophilic hormone

A/B C E

Length varies

Regulatory domainDNAbindingdomain

Nuclear targetingsequence

Hormone-bindingdomain

Functional areas

EA/B

D C