Dr. Kevin Ahern - Oregon State...

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Hormones and Signal Transduction

Dr. Kevin Ahern

Signaling• Outline

Background

BackgroundMembranes

BackgroundMembranesHormones & Receptors

BackgroundMembranesHormones & ReceptorsSecond Messengers

Signaling• Introduction

Needs of a Multicellular Organism

Needs of a Multicellular OrganismResponding to Environment

Needs of a Multicellular OrganismResponding to EnvironmentFood Status

Needs of a Multicellular OrganismResponding to EnvironmentFood StatusDanger

Needs of a Multicellular OrganismResponding to EnvironmentFood StatusDangerGrowth

Needs of a Multicellular OrganismResponding to EnvironmentFood StatusDangerGrowthInjury

Coordination of Cellular/Tissue Responses

Signaling

Signaling• Membranes

Organization of Bilayer Around Cell

Lipid Bilayer Prevents Entry of Most Molecules

Lipid Bilayer

Information must move across membrane

Lipid Bilayer

Information must move across membraneSignal Transduction

Signaling

Signaling Simplest Signaling

Signal

Signaling Simplest Signaling

Signal Response

Nerve System Signaling

Hormones and Signal Transduction• Hormones

Hormones Communicate Messages

Hormones Communicate MessagesHormones are Made in One Part of the Body

Hormones Communicate MessagesHormones are Made in One Part of the BodyExert Effects in Other Part of Body

Hormones Communicate MessagesHormones are Made in One Part of the BodyExert Effects in Other Part of BodyFirst Messengers of a Multi-component Message

Hormones Communicate MessagesHormones are Made in One Part of the BodyExert Effects in Other Part of BodyFirst Messengers of a Multi-component MessageNumerous Chemical Forms

Thyroid Hormone

Epinephrine

Thyroid Hormone

Epinephrine

Thyroid Hormone

Epidermal Growth Factor

Epinephrine

Thyroid Hormone

Epidermal Growth Factor

Progesterone

Hormones and Signal Transduction• Introduction

Cellular Signaling Has Complexity

Hormones and Signal Transduction• Introduction

Cellular Signaling Has Complexity Responses Aimed at Benefitting Organism

Hormones and Signal Transduction• Binding to Receptor

Steroid Hormones Diffuse Through Membrane

Steroid Hormones Diffuse Through MembraneCytosolic Receptor

Receptor Binding Inside Cell

Non-steroid Hormone

Receptor Binding Outside of Cell

Non-steroid Hormone

Receptor Binding Outside of Cell

Numerous Internal Message Carriers

Non-steroid Hormone

Hormones and Signal Transduction• Receptors

Interaction of Hormone with Receptor Changes Receptor

Interaction of Hormone with Receptor Changes ReceptorReceptor Change Alters Interactions with Other Proteins

Changes on Hormone Binding

Hormones and Signal Transduction• Membrane-bound Receptors

G-Protein Coupled Receptor

Hormones and Signal TransductionG-protein Coupled Receptors (GPCRs)

Almost 800 Genes in Human Genome

Almost 800 Genes in Human Genome460 Olfactory

Almost 800 Genes in Human Genome460 Olfactoryβ-adrenergic Receptor

Membrane Bound

Membrane BoundSeven Transmembrane

Domains

Extracellular Domain

Domains

Extracellular Domain

Intracellular Domain

GPCR Action Cycle

Hormone

Binding of Hormone

Hormone

Binding of Hormone

Hormone Structural Change of Receptor

Binding of Hormone

Replacement of GDP by GTP

Binding of Hormone

Replacement of GDP by GTPActivation of an Enzyme

Binding of Hormone

Replacement of GDP by GTPActivation of an Enzyme

Return to Original

Hormones and Signal Transduction• Receipt of Message

Membrane Receptor Proteins Internalize Message

Membrane Receptor Proteins Internalize MessageActivate Synthesis of Second Messengers

Inositol 1,4,5 Trisphosphate (IP3)

Cyclic AMP (cAMP)

Ca++Ca++

Calcium Ions

Cyclic AMP (cAMP)Cyclic GMP (cGMP)

Ca++Ca++

Calcium Ions

Membrane Receptor Proteins Internalize MessageActivate Synthesis of Second MessengersCovalent Modification of “Downstream” Proteins

Ca++Ca++

Calcium Ions

Membrane Receptor Proteins Internalize MessageActivate Synthesis of Second MessengersCovalent Modification of “Downstream” ProteinsAlteration of Gene Expression

Ca++Ca++

Calcium Ions

Membrane Receptor Proteins Internalize MessageActivate Synthesis of Second MessengersCovalent Modification of “Downstream” ProteinsAlteration of Gene ExpressionChange of Enzyme Activities

Ca++Ca++

Calcium Ions

Hormones and Signal Transduction• GPCRs and G-Proteins

Resting State

G-Proteins Bind Guanine Nucleotides (GDP and GTP)

Resting State

G-Proteins Bind Guanine Nucleotides (GDP and GTP)Heterotrimeric - α,β,γ Subunits

Resting State

G-Proteins Bind Guanine Nucleotides (GDP and GTP)Heterotrimeric - α,β,γ SubunitsAssociate with GPCRs

Resting State

G-Proteins Bind Guanine Nucleotides (GDP and GTP)Heterotrimeric - α,β,γ SubunitsAssociate with GPCRsAltered by GPCR’s Binding of Hormone

Resting State

Epinephrine

Resting State

GPCREpinephrine

Epinephrine

GTP GDPResting State

GPCREpinephrine

Epinephrine

GTP GDPResting State

GPCREpinephrine

Epinephrine

Active

Epinephrine

Hormones and Signal Transductionβ-adrenergic Receptor Signaling

Creation of the Second Messenger

Adenylate Cyclase

Also Membrane Bound

Adenylate Cyclase

Also Membrane Bound

Adenylate Cyclase

Activated by binding to α-subunit of G-protein

Also Membrane Bound

Adenylate Cyclase

cAMP + PPi

Also Membrane Bound

Adenylate Cyclase

cAMP + PPi

Second Messenger

Also Membrane Bound

Adenylate Cyclase

cAMP + PPi

Second Messenger

Also Membrane Bound

Adenylate Cyclase

Transmits Signal

Adenylate Cyclase

Hormones and Signal Transduction• Actions of the Second Messenger

4 cAMP

Protein Kinase A

4 cAMP

Protein Kinase A

(Inactive)

4 cAMP

Protein Kinase A

(Inactive)

4 cAMP

Protein Kinase A

(Inactive)

4 cAMP

Catalytic Subunits

Protein Kinase A

(Inactive)

4 cAMP

Regulatory SubunitsCatalytic Subunits

Protein Kinase A

(Inactive)

4 cAMP Activated

Protein Kinase A

(Inactive)

4 cAMP Activated

Protein Kinase A

(Inactive)

4 cAMP Activated

Activity Altered

by Phosphorylation

Metabolic Melody

The Tao of Hormones(To the tune of "The Sound of Silence")

Biochemistry my friendIt's time to study you again

Mechanisms that I need to knowAre the things that really stress me so

"Get these pathways planted firmly in your head,"Ahern said

Let's start with ep-inephrineMembrane proteins are well knownChanged on binding this hormoneRearranging selves without protest

Stimulating a G alpha STo go open up and displace its GDP

With GTPBecause of ep-inephrine

Active G then moves a ways Stimulating ad cyclase

So a bunch of cyclic AMP Binds to kinase and then sets it free

All the active sites of the kinases await Triphosphate

Because of ep-inephrine

Biochemistry my friendIt's time to study you again

Mechanisms that I need to knowAre the things that really stress me so

"Get these pathways planted firmly in your head,"Ahern said

Let's start with ep-inephrineMembrane proteins are well knownChanged on binding this hormoneRearranging selves without protest

Stimulating a G alpha STo go open up and displace its GDP

With GTPBecause of ep-inephrine

Active G then moves a ways Stimulating ad cyclase

So a bunch of cyclic AMP Binds to kinase and then sets it free

All the active sites of the kinases await Triphosphate

Because of ep-inephrine

Muscles are affected then Breaking down their glycogen So they get a wad of energy In the form of lots of G-1-P

And the synthases that could make a glucose chain All refrain

Because of ep-inephrineNow I've reached the pathway end

Going from adrenalin Here's a trick I learned to get it right Linking memory to flight or fright

So the mechanism that's the source of anxious fears Reappears

When I make ep-inephrine

Dr. Kevin Ahern - Oregon State...

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