g-protein-linked receptors
DESCRIPTION
Manifestation of Novel Social Challenges of the European Union in the Teaching Material of Medical Biotechnology Master’s P rogrammes at the University of Pécs and at the University of Debrecen Identification number : TÁMOP-4.1.2-08/1/A-2009-0011. - PowerPoint PPT PresentationTRANSCRIPT
Manifestation of Novel Social Challenges of the European Unionin the Teaching Material ofMedical Biotechnology Master’s Programmesat the University of Pécs and at the University of DebrecenIdentification number: TÁMOP-4.1.2-08/1/A-2009-0011
G-PROTEIN-LINKED RECEPTORS
Tímea Berki and Ferenc BoldizsárSignal transduction
Manifestation of Novel Social Challenges of the European Unionin the Teaching Material ofMedical Biotechnology Master’s Programmesat the University of Pécs and at the University of DebrecenIdentification number: TÁMOP-4.1.2-08/1/A-2009-0011
TÁMOP-4.1.2-08/1/A-2009-0011
Nomenclature• G-protein-coupled receptors (GPCRs) • Seven-transmembrane domain
receptors• 7-TM receptors• Heptahelical receptors • Serpentine receptor • G protein-linked receptors (GPLR)
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Ligand-binding
Gα C-terminal tail
Other Gα surfaces
Helix 8 (Gβ-binding)
Gα -binding
Interaction surface
IL1 IL2 IL3
EL1 EL3EL2 Extracellular loops (EL1-3)
Intracellular loops (IL1-3)
N
C
GRK phosphorylation(Desensitization)
PKC phosphorylation(Desensitization)
PKC phosphorylation(Desensitization)
Palmitoylation(Lipid raft localization)
N-Glycosylation(Receptor folding, trafficking)
E/DRY Motif(Receptor activity and
protein-protein interactions)
Plasma membrane
TM1
TM2
TM3
TM4
TM5
TM6
TM7
Transmembrane helix(TM1-7)
TM4
7-transmembrane-spanning receptors (7-TM)
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GPCR
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Structure of 7-TM receptorsSide perspective
Intracellular persective
TM1
TM4
TM5
TM6
TM7
Helix 8
IL 1IL2
IL3
EL1EL2
EL 3N
C TM2
TM3
Intracellular loops
Extracellular loops
TM1
TM2
TM3 TM
4
TM5
TM6
TM7
Helix 8
IL1
IL3
EL1 EL2
EL3N
C
Ga-bindingsurface
Non-covalentbond
IL2
TM1
TM2 TM
4
Helix 8
IL1
IL2
IL3
EL1
EL2
EL3NC
TM7
TM6
TM3
TM5
Ga
TM1
TM5
TM6TM
7
Helix 8
N
CTM4
TM2 Gα
TM3
GaC-terminaltail of Ga
Agonist
Active GPCRInactive GPCR
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GPCR subtypes• Class A (or 1) – Rhodopsin-like • Class B (or 2) – Secretin receptor family • Class C (or 3) – Metabotropic
glutamate/pheromone • Class D (or 4) – Fungal mating pheromone
receptors • Class E (or 5) – Cyclic AMP receptors • Class F (or 6) – Frizzeled/Smoothened
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GDP
ba
b
GTP
a
GTP
ba
GDP
ba
Plasma membrane
Cytoplasm
GDP GTP
G-protein coupled receptor(GPCR)
Signal molecule
Inactive G-protein
Activated G-protein subunits
GTP
ba
Activation of G-protein-coupled receptors (GPCR)
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GDP
ba
b
GTP
Gia
G-protein coupled receptor(GPCR)
PhospholipasesIon channels
Activates Rho
Ion channelsPI3K
PhospholipasesAdenylyl cyclasesReceptor kinases
GTP
GsaGTP
Gqa
GTP
G12/13a
GTP
a
Ca2+
PLCPIP2 DAG
IP3
cAMP
Adenylylcyclase
ATPcAMP
Adenylylcyclase
ATP
Plasma membrane
Cytoplasm
G-proteins
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G-protein heterotrimer
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Catecholamine hormon synthesis
CO2–+H3N
OHTyrosine
Tyrosinehydroxylase
CO2–+H3N
OHDihydroxy
phenilalanine(L-DOPA)
OH DOPAdecarboxylase
Dopamine
+H3N
OH
OH
Dopamineβ-hydroxylase
Dopamine
+H3N
OH
OHHO Phenethanolamine
N-methyltransferase
Epinephrine
N
OH
OHHO
H2+
H3C
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Epinephrine and analogues
HO
HO
OH
CH3
HN
Epinephrine (adrenaline)Tyramine HCL
HO
NH2
.HCLOH
CH3
HN
Ephedrine sulphate
CH3
2
.H2SO4
Pseudoephedrine HCL
OH
CH3
HN
CH3
.HCL
Dexamfetamine sulfate
NH2
CH3
2
.H2SO4
Amfetamine sulfate
NH2
CH3
2
.H2SO4
Phenylethanolamine sulfate
NH2
OH
2
.H2SO4
Isoprenaline HCL
NOH
.HCLHHO
HO
CH3
CH3
Orciprenaline sulfate
NOH HHO
OH
CH3
CH3.H2SO4
2
.H2SO4
2Salbutamol sulfate
NOH H
HO CH3
CH3HOCH3
.H2SO4
2Terbutaline sulfate
NOH H CH3
CH3CH3
HO
OH
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cAMP-PKA pathway
PO4 gatedchannel
Gα gatedchannel
cAMP gatedchannel
Receptor
Inactive PKA ActivatedPKA
GTP
ba
Adenylylcyclase
RR
CC
cAMPcAMPcAMP
cAMP
RR
CC
CC
RcAMP
cAMP
RcAMPcAMP
CRE
CREB
cAMP Response Element
Gene expressionP
CREBP
CREB
ATP cAMP
GTP
a
Nucleus
PcAMPGTP
a
P
ADPATP
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Primary Action of Epinephrine in a Liver Cell
AcetylcholineStress signal Fuel for „fight or flight”
Protein Kinase A
Glucose-6-Phosphatase
Pyr Kinase
Fructose-2,6-bisphosphatase
Pyruvate
PEP
Fructose-1,6-bisP
Fructose-6-PFructose-2,6-bisP
Fructose-1,6-bisphosphatase PFK-1
Glucose-6-P
Glucose
Glucose-1-P Glycogen
GlucogenPhosphoryla
se
Glucogen Synthase
P
P
P
Phosphorylase
Kinase AP
PcAMPATP
Adenylate Cyclase
GDP
bas
EpinephrineReceptor
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Glucagon signalingPANCREAS Glucose low in blood
Protein Kinase A
Glucose-6-Phosphatase
Pyr Kinase
Fructose-2,6-bisphosphatase
Pyruvate
PEP
Fructose-1,6-bisP
Fructose-6-PFructose-2,6-bisP
Fructose-1,6-bisphosphatase PFK-1
Glucose-6-P
Glucose
Glucose-1-P Glycogen
GlycogenPhosphoryla
se
Glycogen Synthase
P
P
P
P
cAMPATP
Adenylate Cyclase
GDPbas
Glucagon(Epinephrin
e)Receptor
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Serotonin receptor
Serotonin receptor → G-protein → adenylyl cyclase → ATP → cAMP → PKA → cAMP Response Element (CRE) → Gene expression
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Types of serotonin receptor
Family Mechanism Potential
5-HT1 Decreasing cellular levels of cAMP Inhibitory
5-HT2 Increasing cellular levels of IP3 and DAG Excitatory
5-HT3 Depolarizing plasma membrane Excitatory
5-HT4 Increasing cellular levels of cAMP Excitatory
5-HT5 Decreasing cellular levels of cAMP Inhibitory
5-HT6 Increasing cellular levels of cAMP Excitatory
5-HT7 Increasing cellular levels of cAMP Excitatory
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Receptor desensitization
GRKATP ADP
ArrestinP PPP PP
G-protein linked receptor kinase
Activated receptor Desensitized receptor