Cell Biol Lecture-1
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Signal Transduction Section of Cell Biology
Signaling by G Proteins: –– Heterotrimeric G Proteins –– Ras Superfamily Small GTPases Copyright (c) by W. H. Freeman and Company
Celltocell communication by extracellular signaling usually involves six steps (1) synthesis of the signaling molecule by the signaling cell (2) release of the signaling molecule by the signaling cell (3) transport of the signal to the target cell (4) detection of the signal by a specific receptor protein (5) a change in cellular metabolism, function, or development triggered by the receptorsignal complex ❚ (6) removal of the signal, which usually terminates the cellular response ❚ ❚ ❚ ❚ ❚
Copyright (c) by W. H. Freeman and Company
Signaling molecules operate over various distances in animals
Receptor proteins exhibit ligandbinding and effector specificity Copyright (c) by W. H. Freeman and Company
Hormones can be classed based on their solubility and receptor location
Copyright (c) by W. H. Freeman and Company
Cellsurface receptors belong to four major classes
Copyright (c) by W. H. Freeman and Company
Cellsurface receptors belong to four major classes
Copyright (c) by W. H. Freeman and Company
Signaling by Heterotrimeric G Proteins
Copyright (c) by W. H. Freeman and Company
History of Transmembrane Signaling ❚ (1) Earl W. Sutherland’s Second Messenger Hypothesis ❚ (2) Fischer and Kreb’s Reversible Protein Phosphorylation as a Biological Regulatory Mechanism ❚ (3) Martin Rodbell’s Transducer Model ❚ (4) Alfred G. Gilman’s Discovery of G Proteins
Copyright (c) by W. H. Freeman and Company
Earl W. Sutherland’s Second Messenger Hypothesis Varied Stimuli
Endocrine gland
Hormone (first messenger)
Inactivated hormone
5’AMP
Adenyl cyclase or X
cAMP or Y (second messenger(s))
Enzymes, permeability, etc. ... Physiological responses including Steroids, Thyroid hormones, etc.
Copyright (c) by W. H. Freeman and Company
Fischer and Krebs’ Reversible Protein Phosphorylation Adrenaline Receptor cyclase cAMP
ATP
PKA Nonactivated Phosphorylase kinase
Activated Phosphorylase kinase
Phosphorylase b (inactive)
Phosphorylase a (active) Glycogen + Pi
Copyright (c) by W. H. Freeman and Company
Glucose1P
Rodbell’s Transducer Model
Hormone
GTP
Discriminator
Mg 2+
Transducer
GDP
Copyright (c) by W. H. Freeman and Company
ATP Amplifier cAMP
Gilman’s Purification of G Proteins And G Protein Cycle
GDP
GαGDP.βγ
+
GαGTP
GαGDP βγ
GTP
RGS
Copyright (c) by W. H. Freeman and Company
Pi
βγ
Effectors Effectors
G proteincoupled receptors ❚ Many different mammalian cellsurface receptors are coupled to a trimeric signaltransducing G protein ❚ Ligand binding activates the receptor, which activates the G protein, which activates an effector enzyme to generate an intracellular second messenger ❚ All G proteincoupled receptors (GPCRs) contain 7 membranespanning regions with their Nterminus on the exoplasmic face and Cterminus on the cytosolic face ❚ GPCRs are involved in a range of signaling pathways, including light detection, odorant detection, and detection of certain hormones and neurotransmitters Copyright (c) by W. H. Freeman and Company
G proteincoupled receptors
Copyright (c) by W. H. Freeman and Company
G Proteincoupled Receptors
Group V
olfactory R, adenosine R, cannabinoid R, ...... serotonin R, adrenergic R, dopamine R, histamine R, muscarinic R, ...... rhodopsins, endothelin R, thyrotropin releasing hormone R, ...... bradykinin R, ...... angiotensin R, chemokine R, thrombin R, ......
Group VI
melatonin R, ......
Group I
calcitonin R, ......
Group I Group II
Family A
Group III Group IV
Group III
parathyroid hormone/parathyroidrelatedpeptide R glucagon R, growth hormone releasing hormone R, pituitary adenylyl cyclase activating peptide R, ......
Group IV
latrotoxin R, ......
Group II
GPCR
Family B
Group II
metabotropic glutamate R, ...... calcium R, ......
Group III
GABAB R, ......
Group I
Family C Family D Family E Family F
STE2 R, ...... STE3 R, ...... Copyright (c) by W. H. Freeman and Company cAMP R, ......
Structure of GPCR and G Protein
Copyright (c) by W. H. Freeman and Company
Structure of GPCR and G Protein
Copyright (c) by W. H. Freeman and Company
Demonstration of functional domains in G proteincoupled receptors
Copyright (c) by W. H. Freeman and Company
Heterotrimeric G Proteins
Copyright (c) by W. H. Freeman and Company
G Protein α Subunits αs α olf α i1 α i3 α i2 α oA α oB α t1 α t2 αg
αs
αi
αz αq α 11 α 14 α 15 α 16 α 12 60
Copyright (c) by W. H. Freeman and Company
80
% amino acid identity
α 13
100
αq
α 12
Gs: linking βadrenergic receptors and adenylyl cyclase
Copyright (c) by W. H. Freeman and Company
Some bacterial toxins irreversibly modify G proteins
Copyright (c) by W. H. Freeman and Company
The structure of adenylyl cyclase
Copyright (c) by W. H. Freeman and Company
The structure of Gsα∙GTP complexed with two fragments from the adenylyl cyclase catalytic domain
Copyright (c) by W. H. Freeman and Company
Kinase cascades permit multienzyme regulation and amplify hormone signals
Copyright (c) by W. H. Freeman and Company
Cellular responses to cAMP vary among different cell types
Copyright (c) by W. H. Freeman and Company
Gt (Transducin): Visual Transduction Light
Receptor (rhodopsin)
αt β γ G protein (transducin)
cGMP phosphodiesterase
Cyclic nucleotide gated cation channel
Membrane hyperpolarization
cGMP 5'GMP
Lower cGMP Copyright (c) by W. H. Freeman and Company
Sense of light
Visual Transduction
Copyright (c) by W. H. Freeman and Company
Gi: Inhibiting Certain Isotypes of Adenylyl Cyclases
Copyright (c) by W. H. Freeman and Company
Gq: Stimulating Phospholipase C β
Copyright (c) by W. H. Freeman and Company
Hormoneinduced release of Ca2+ from the ER is mediated by IP3
Copyright (c) by W. H. Freeman and Company
IP3induced Ca2+ increases are used to trigger various responses in different cells
Copyright (c) by W. H. Freeman and Company
The effects of many hormones are mediated by second messengers
Copyright (c) by W. H. Freeman and Company
Effector Enzymes
αs αolf αi1 αi3 αi2 αoA αoB αt1 αt2 αg αz αq α11 α14 α15 α16 α12 60
80
α13
100
Interacting Proteins
Adenylyl cyclases Src tyrosine kinase Adenylyl cyclases (I, V, VI) Src tyrosine kinase Adenylyl cyclases (I) ? cGMP-specific phosphodiesterase
Calnuc, Tubulin
Adenylyl cyclases (I, V, VI) ? Phospholipase C-β (β1≥β3>β2) Btk tyrosine kinase
Rap1GAP, GRIN1, Eya2
Phospholipase C-β (β1≥β3>β2) ? Btk tyrosine kinase ? Btk tyrosine kinase Copyright (c) by W. H. Freeman and Company ?
Rap1GAPII, Calnuc, Tubulin, Pcp2, LGN, GRIN1, Eya2 Rap1GAPII, Tubulin, Pcp2, LGN, GRIN1
Tubulin
Gap1 rasGAP Cadherin p115 RhoGEF/Lsc Cadherin
Gβγ: Regulation of certain effectors by Gβγ and various Gα ∙GTP complexes contributes to integration of cellular metabolism
Copyright (c) by W. H. Freeman and Company
Direct effectors of Gβγ Enzymes Adenylyl cyclases Phospholipase Cβ PI3Kγ GRK Btk
Ion channels K+ (GIRK) Ca2+ (N, P/Q) Copyright (c) by W. H. Freeman and Company
From plasma membrane to nucleus ❚ Many cellular responses induced by watersoluble hormones, growth factors, and neurotransmitters result from their effects on gene expression ❚ Such pathways usually involve activation of protein kinases that directly or indirectly phosphorylate specific transcription factors
Copyright (c) by W. H. Freeman and Company
CREB links cAMP signals to transcription
Copyright (c) by W. H. Freeman and Company
Signaling by G Proteins: –– Heterotrimeric G Proteins –– Ras Superfamily Small GTPases Copyright (c) by W. H. Freeman and Company
Celltocell communication by extracellular signaling usually involves six steps (1) synthesis of the signaling molecule by the signaling cell (2) release of the signaling molecule by the signaling cell (3) transport of the signal to the target cell (4) detection of the signal by a specific receptor protein (5) a change in cellular metabolism, function, or development triggered by the receptorsignal complex ❚ (6) removal of the signal, which usually terminates the cellular response ❚ ❚ ❚ ❚ ❚
Copyright (c) by W. H. Freeman and Company
Signaling molecules operate over various distances in animals
Receptor proteins exhibit ligandbinding and effector specificity Copyright (c) by W. H. Freeman and Company
Hormones can be classed based on their solubility and receptor location
Copyright (c) by W. H. Freeman and Company
Cellsurface receptors belong to four major classes
Copyright (c) by W. H. Freeman and Company
Cellsurface receptors belong to four major classes
Copyright (c) by W. H. Freeman and Company
Signaling by Heterotrimeric G Proteins
Copyright (c) by W. H. Freeman and Company
History of Transmembrane Signaling ❚ (1) Earl W. Sutherland’s Second Messenger Hypothesis ❚ (2) Fischer and Kreb’s Reversible Protein Phosphorylation as a Biological Regulatory Mechanism ❚ (3) Martin Rodbell’s Transducer Model ❚ (4) Alfred G. Gilman’s Discovery of G Proteins
Copyright (c) by W. H. Freeman and Company
Earl W. Sutherland’s Second Messenger Hypothesis Varied Stimuli
Endocrine gland
Hormone (first messenger)
Inactivated hormone
5’AMP
Adenyl cyclase or X
cAMP or Y (second messenger(s))
Enzymes, permeability, etc. ... Physiological responses including Steroids, Thyroid hormones, etc.
Copyright (c) by W. H. Freeman and Company
Fischer and Krebs’ Reversible Protein Phosphorylation Adrenaline Receptor cyclase cAMP
ATP
PKA Nonactivated Phosphorylase kinase
Activated Phosphorylase kinase
Phosphorylase b (inactive)
Phosphorylase a (active) Glycogen + Pi
Copyright (c) by W. H. Freeman and Company
Glucose1P
Rodbell’s Transducer Model
Hormone
GTP
Discriminator
Mg 2+
Transducer
GDP
Copyright (c) by W. H. Freeman and Company
ATP Amplifier cAMP
Gilman’s Purification of G Proteins And G Protein Cycle
GDP
GαGDP.βγ
+
GαGTP
GαGDP βγ
GTP
RGS
Copyright (c) by W. H. Freeman and Company
Pi
βγ
Effectors Effectors
G proteincoupled receptors ❚ Many different mammalian cellsurface receptors are coupled to a trimeric signaltransducing G protein ❚ Ligand binding activates the receptor, which activates the G protein, which activates an effector enzyme to generate an intracellular second messenger ❚ All G proteincoupled receptors (GPCRs) contain 7 membranespanning regions with their Nterminus on the exoplasmic face and Cterminus on the cytosolic face ❚ GPCRs are involved in a range of signaling pathways, including light detection, odorant detection, and detection of certain hormones and neurotransmitters Copyright (c) by W. H. Freeman and Company
G proteincoupled receptors
Copyright (c) by W. H. Freeman and Company
G Proteincoupled Receptors
Group V
olfactory R, adenosine R, cannabinoid R, ...... serotonin R, adrenergic R, dopamine R, histamine R, muscarinic R, ...... rhodopsins, endothelin R, thyrotropin releasing hormone R, ...... bradykinin R, ...... angiotensin R, chemokine R, thrombin R, ......
Group VI
melatonin R, ......
Group I
calcitonin R, ......
Group I Group II
Family A
Group III Group IV
Group III
parathyroid hormone/parathyroidrelatedpeptide R glucagon R, growth hormone releasing hormone R, pituitary adenylyl cyclase activating peptide R, ......
Group IV
latrotoxin R, ......
Group II
GPCR
Family B
Group II
metabotropic glutamate R, ...... calcium R, ......
Group III
GABAB R, ......
Group I
Family C Family D Family E Family F
STE2 R, ...... STE3 R, ...... Copyright (c) by W. H. Freeman and Company cAMP R, ......
Structure of GPCR and G Protein
Copyright (c) by W. H. Freeman and Company
Structure of GPCR and G Protein
Copyright (c) by W. H. Freeman and Company
Demonstration of functional domains in G proteincoupled receptors
Copyright (c) by W. H. Freeman and Company
Heterotrimeric G Proteins
Copyright (c) by W. H. Freeman and Company
G Protein α Subunits αs α olf α i1 α i3 α i2 α oA α oB α t1 α t2 αg
αs
αi
αz αq α 11 α 14 α 15 α 16 α 12 60
Copyright (c) by W. H. Freeman and Company
80
% amino acid identity
α 13
100
αq
α 12
Gs: linking βadrenergic receptors and adenylyl cyclase
Copyright (c) by W. H. Freeman and Company
Some bacterial toxins irreversibly modify G proteins
Copyright (c) by W. H. Freeman and Company
The structure of adenylyl cyclase
Copyright (c) by W. H. Freeman and Company
The structure of Gsα∙GTP complexed with two fragments from the adenylyl cyclase catalytic domain
Copyright (c) by W. H. Freeman and Company
Kinase cascades permit multienzyme regulation and amplify hormone signals
Copyright (c) by W. H. Freeman and Company
Cellular responses to cAMP vary among different cell types
Copyright (c) by W. H. Freeman and Company
Gt (Transducin): Visual Transduction Light
Receptor (rhodopsin)
αt β γ G protein (transducin)
cGMP phosphodiesterase
Cyclic nucleotide gated cation channel
Membrane hyperpolarization
cGMP 5'GMP
Lower cGMP Copyright (c) by W. H. Freeman and Company
Sense of light
Visual Transduction
Copyright (c) by W. H. Freeman and Company
Gi: Inhibiting Certain Isotypes of Adenylyl Cyclases
Copyright (c) by W. H. Freeman and Company
Gq: Stimulating Phospholipase C β
Copyright (c) by W. H. Freeman and Company
Hormoneinduced release of Ca2+ from the ER is mediated by IP3
Copyright (c) by W. H. Freeman and Company
IP3induced Ca2+ increases are used to trigger various responses in different cells
Copyright (c) by W. H. Freeman and Company
The effects of many hormones are mediated by second messengers
Copyright (c) by W. H. Freeman and Company
Effector Enzymes
αs αolf αi1 αi3 αi2 αoA αoB αt1 αt2 αg αz αq α11 α14 α15 α16 α12 60
80
α13
100
Interacting Proteins
Adenylyl cyclases Src tyrosine kinase Adenylyl cyclases (I, V, VI) Src tyrosine kinase Adenylyl cyclases (I) ? cGMP-specific phosphodiesterase
Calnuc, Tubulin
Adenylyl cyclases (I, V, VI) ? Phospholipase C-β (β1≥β3>β2) Btk tyrosine kinase
Rap1GAP, GRIN1, Eya2
Phospholipase C-β (β1≥β3>β2) ? Btk tyrosine kinase ? Btk tyrosine kinase Copyright (c) by W. H. Freeman and Company ?
Rap1GAPII, Calnuc, Tubulin, Pcp2, LGN, GRIN1, Eya2 Rap1GAPII, Tubulin, Pcp2, LGN, GRIN1
Tubulin
Gap1 rasGAP Cadherin p115 RhoGEF/Lsc Cadherin
Gβγ: Regulation of certain effectors by Gβγ and various Gα ∙GTP complexes contributes to integration of cellular metabolism
Copyright (c) by W. H. Freeman and Company
Direct effectors of Gβγ Enzymes Adenylyl cyclases Phospholipase Cβ PI3Kγ GRK Btk
Ion channels K+ (GIRK) Ca2+ (N, P/Q) Copyright (c) by W. H. Freeman and Company
From plasma membrane to nucleus ❚ Many cellular responses induced by watersoluble hormones, growth factors, and neurotransmitters result from their effects on gene expression ❚ Such pathways usually involve activation of protein kinases that directly or indirectly phosphorylate specific transcription factors
Copyright (c) by W. H. Freeman and Company
CREB links cAMP signals to transcription
Copyright (c) by W. H. Freeman and Company
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