Haploid a- and -cells form shmoos in response to chemical signals Shmoos mate to form diploid a/cell Examples of: - “differentiated” cell types (a-, -, and a/-cells) cell-cell adhesion -cell-cell signaling Human body consists of trillions of cells, 200+ specialized cell types that must differentiate (next time) and communicate (today) with one another Cell-cell communication required to coordinate: - physiology and metabolism - behavior -growth, proliferation, and differentiation ECB 16-1 Mating dance of a budding yeast (S.cerevisiae)… Multicellularity: From cells to tissues to organisms shmoos
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Haploid a- and -cells form shmoos in response to chemical signals Shmoos mate to form diploid a/ cell Examples of: - “differentiated” cell types (a-,
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Haploid a- and -cells form shmoos in response to chemical signals
Human body consists of trillions of cells, 200+ specialized cell types that must differentiate (next time) and communicate (today) with one another
Cell-cell communication required to coordinate:- physiology and metabolism- behavior-growth, proliferation, and differentiation
ECB 16-1
Mating dance of a budding yeast (S.cerevisiae)…
Multicellularity: From cells to tissues to organisms
shmoos
“Neuronal”
Cell body of neuron
Post-synaptictarget (muscle,
neuron, etc)
Axon
Synapse
Action potential
Basic categories of cell-cell signaling in animals
ECB 16-3
“Paracrine” (local)ex. inflammation
Signaling cell
Target cells
“Autocrine”
“Contact-mediated” (short range)ex. - nerve cell production
Signaling cell
Target cell
(ex.-hormones)“Endocrine” (long distance)
Endocrine (signaling) cell
Target cells
Bloodstream
hormone
Cellular response depends on specific combination of signals
ECB 16-6
No signal often results in activation of apoptosis
Common features of cell-cell signaling pathways
Other signals
ECB 16-7
Receptors for diffusible signals can be intracellular or surface
Small non-polar molecules Large polar molecules
Plasma membran
e
cross plasma membrane by simple diffusion
And bind to intra- cellular receptors
…cannot cross membrane
They bind cell surface receptors
Membrane receptors for hydrophilic signaling molecules activate a wide variety of intracellular “signal transduction” pathways, including gene regulation
Most receptors for hydrophobic signaling molecules act in nucleus to regulate gene transcription
ECB 16-9
Transcription
Transcription
Intracellular signals
Intracellular receptors Cell surface receptors
A few examples of hydrophobic hormonesECB 16-11
Responses mediated by a conserved family of “steroid” receptors
HO
OH
Estradiol
OH
O
Testosterone
HO O COO-CH2 C
H
NH3+
II
II
Thyroid hormone
HO
Cholesterol
CH2OH
O
HO
C=O
OH
Cortisol
(not hormone)
Responses to hydrophobic hormones are mediated by intracellular receptors
ECB 16-12
Transcription
Translation
Cytoplasm
Nucleus
Nuclear envelope
Plasma membrane Lipophilic hormone carried
in blood
Hormone binds intracellular receptor inducing receptor dimerization and activation
Complex is imported into nucleus
Binds to “hormone response element” to regulate gene expression
Intracellular receptor
Promoter Target gene“Hormone response element”
Target cell
Receptor G-protein(inactive)
Target(inactive)
G-protein linked receptor
Cell-surface receptors - three classes
ECB 16-14
Receptor(active)
G-protein(active)
Target(inactive)
Signaling ligand
Signaling ligand
Catalytic domain(active)
Signaling ligand
Ions
Catalytic domain(active)
Enzyme-linked receptor
Ion channel-linked receptor
Receptor(active)
G-protein(active)
Target(active)
Activation of surface receptor can cause fast (cytoplasmic) or slow (transciptional) changes
Review: phosphorylation and GTPases as molecular switches
ECB 16-15
ADP
ATP Pi
PhosphataseKinase
Pi
GAPGEF
GTP
On
P
On
Energy (in the form of ATP or GTP hydrolysis) used to activate (or inactivate) signaling molecules
Energy use allows transient, high affinity/specificity interactions
Signaling with GTPasesSignaling with phosphorylation
Signal in Signal in
Signal activates protein kinase
Signal activates GEF
Signal out
Signal out
GTP
GDP
GDP
Off
Signaling GTPase
Off
Signaling protein
“Heterotrimeric G-proteins” mediate many cell signals
GDP
See ECB 16-17
G, G subunits
G binds guanine nucleotide
Receptor acts as GEF, activating G-protein
Activated G- and G regulate targets
G inactivated by GTP hydrolysis, subunits reassociate
GTP
+
GTP
GDPPi
G
(inactive GDP form)
ActiveG and G
(GTP form)
Heterotrimeric G-proteins
Downstream targets
Multiple G-proteins with distinct -, -, and -subunits (>20 known)
“Gs” stimulates or activates effectors
“Gi” inhibits effectors
“Gq” mediates Ca2+ signaling
G-protein –GDP(inactive)
GDP
Plasma membrane
Cytoplasm
Extracellular space
See ECB 16-16
“Heterotrimeric G-proteins” are activated by a family of “Seven-pass” transmembrane
receptors
Inactive receptor
Seven transmembrane domains (-helices)
Extracellular ligand-binding domain (N-terminal)
Cytoplasmic “effector” domain
Activated receptor acts as GEF to activate “heterotrimeric G-protein”
Ligand binding domain
Effector domain
1 2 3 4 5 6 7
Seven-pass
receptor
“Heterotrimeric G-proteins” are activated by a family of “Seven-pass” transmembrane
receptors
ECB 16-18 thru 16-18
Binding of ligand activates receptor
G-protein –GDP(inactive)
Inactive target
GDP
GTP
Active receptor
“Heterotrimeric G-proteins” are activated by a family of “Seven-pass” transmembrane
receptors
Binding of ligand activates receptor
Heterotrimeric G-protein binds activated receptor
Activated receptor acts as GEF for heterotrimeric G-protein
Activated components (- and /-) regulate downstream targets