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Mechanism of hormone action

Mechanism of hormone Mechanism of hormone actionaction

ผศ.ดร.พญ.สุวัฒณี คุปติวฒิุ

ภาควิชาสรีรวิทยา

คณะแพทยศาสตรศิริราชพยาบาล

AimsAimsWhat is hormone receptorhormone receptor

Type of hormone receptorshormone receptors

-- cell surface receptorcell surface receptor

-- intracellular receptorintracellular receptor

SignalingSignaling via hormone receptorsvia hormone receptors

TypeType of of second messengerssecond messengers

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A protein of target cells that binds

to a specific hormone

HormoneHormone receptorreceptor

Target cells: Any cells that have

specific receptor for hormone

HormoneHormone and target cells specificityand target cells specificity

SpecificitySpecificity

H + R HR complexHR complex

AffinityAffinityNumberNumber

ReversibleReversible

Single H Different R Different Effects+

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Hormone actionHormoneHormone actionaction

One hormoneOne hormone

Multiple actionsMultiple actions

One actionsOne actions

Multiple hormonesMultiple hormones

Gene expression

Signal transduciton

Glucose utilization

Blood pressure

AldosteroneAngiotensin II

There are 2 groups of hormone receptors

There are 2 groups of hormone There are 2 groups of hormone receptorsreceptors

CCellell--surface receptorssurface receptors

Intracellular receptorsIntracellular receptors

Polypeptide hormones: GH, Insulin, GnRH, Gn

Catecholamines: E, NE

Steroid hormone

Thyroid Hormone

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Cell-surface receptorsCellCell--surface receptorssurface receptors

Glycoprotein that cross the cell membrane

to create extracellular and intracellular domains. Glycoprotein that cross the cell membrane

to create extracellular and intracellular domains.

Extracellular domain

Intracellular domain

•• CellCell--surface receptorssurface receptors

G-protein coupled receptor

Receptor regulating ion channels

Receptor containing tyrosine kinase

Receptor associated tyrosine kinase

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GHReceptor

Receptor associated tyrosine kinase

β-Adrenergic Receptor

G-protein coupled receptor

Receptor regulating ion channels Insulin

Receptor

Receptor containing tyrosine kinase

•• CellCell--surface receptorssurface receptors

Extracellular

CytoplasmicPTH,LH, Glucagon

Receptor

Three stages of cell signalingThree stages of cell signaling• Hormone recognition (1st messenger)• Signal generation (2nd messenger)• Alteration of intracellular processes

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G protein couple receptorG protein couple receptor

G proteinG proteinG protein

α α subunitsubunit

β, γ β, γ subunitssubunits

StimulatorStimulatorbind to GDPbind to GDP

InhibitorInhibitor

AdenylylAdenylyl cyclasecyclasePLCPLCIon channelsIon channels

AdrenergicAdrenergic

G protein couple receptorG protein couple receptor

MovieMovieHormone action Hormone action movmov

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Type of G alpha subunits

Type of G alpha subunits

ααii ααSS ααqq α α 12,1312,13

AdenylylAdenylyl cyclasecyclaseAdenylylAdenylyl cyclasecyclase PLCPLC RhoRho

++ ++ ++--

Second MessengersSecond Messengers

Chemical signal which connect to other

protein to co-ordinate the activities of

other molecule

Chemical signal which connect to other

protein to co-ordinate the activities of

other molecule

G protein second messengersAdenylyl cyclase

Guanylyl cyclasePhospholipase C

Ion channels

cAMPcGMPIP3, DAG

2nd messenger2nd messengerEnzymeEnzyme

Ca2+Phospholipase A2 Arachidonic acids

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Second MessengersSecond Messengers

Amplification signalsAmplification signals Cellular responsesCellular responses

Signalamiplification.swf

cGMP Second Messenger

Guanylate cyclase

cGMP

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Action of epinephrine on liver cellAction of epinephrine on liver cell

CPhospholipase A2

Arachidonic acid- PG- TX- Leu

Phospholipase CPhospholipase C

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Receptor containing tyrosine kinaseReceptor containing tyrosine Receptor containing tyrosine kinasekinase

Receptorauto-phosphorylation

Insulin Receptor

GH GH GH GH

P PPP P

P

P

PP

JAK2 JAK2

mRNA

mRNA

IGF

GHReceptor

Plasmamembrane

Receptor Associated with Tyrosine Kinase

STAT = Signal transducer and activators of transcription JAK2 = Janus kinase (cytoplasmic tyrosine kinase)

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Intracellular ReceptorsIntracellular ReceptorsIntracellular Receptors

Steroid Receptors

Thyroid hormone Receptors

Estrogen

Progesterone

Glucocorticoid

DNA HormoneBinding

NH2COOHA/B C D E F

Interact with othertranscription factors

DNAbinding

domain

Hormonebinding

NH2 COOH

Intracellular receptor modelCytoplasmic receptor-thyroid H, vit D, aldosterone

Intracellular receptor modelCytoplasmic receptor-thyroid H, vit D, aldosterone

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Steroid hormone actionSteroid hormone Steroid hormone actionaction

HRE GeneGeneGTF

Pathway I: ER, PR, GR, ARPathway I: ER, PR, GR, AR

HRE GeneGeneGTF

Basal

Stimulated

Hormone

Hormone receptor

Co-activator

GTF General transcriptionfactors

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Pathway II: thyroid hormone, vitamin DPathway II: thyroid hormone, vitamin D

HRE GeneGene

repressor

HRE GeneGeneGTF

Basal

HRE GeneGene

GTF Stimulated

Co-repressorRXR Hormone

Hormone receptor

Regulation of transcription by hormone not entering cellsRegulation of transcription by hormone not entering cells

Proteinkinase A

Transcription

Translation

cAMP

CRE = cAMP regulatory element

CREB = cAMP response element binding protein

CREB-P

or

P = RNA polymerase

CREB

F = transcription factor = CREB-P

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Peptide hormonesPeptide hormones

Two General Classes of HormonesSteroid hormonesSteroid hormones

Peptide hormonesPeptide hormones

SlowerSlower

FasterFaster

Termination of hormone actionPeptide hormonesPeptide hormones

•• Hormones are degrade by blood enzymesHormones are degrade by blood enzymes

•• Plasma membrane-hormone-receptor complex was internalized by endocytosis and degraded by lysosomal enzymes

Steroid hormonesSteroid hormones

•• In the absence of further stimulation, newly synthesized RNA and proteins are degraded by cytoplasmic enzyme actions

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Practice Questions

Which of the following is a steroid hormone?

A. InsulinB. TestosteroneC. EpinephrineD. OxytocinE. Growth hormone

AnsAns: B: B

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The transcription of new messenger RNA is a function of

A. steroid hormones.B. amino acid-based hormones.C. pancreatic hormones.D. catecholamines.E. pituitary gland hormones.

AnsAns: A: A