Essential Cell Biology FOURTH EDITION

Download Report

Transcript Essential Cell Biology FOURTH EDITION

Alberts • Bray • Hopkin • Johnson • Lewis • Raff • Roberts • Walter
Essential
Cell Biology
FOURTH EDITION
Chapter 16
Cell Signaling
Copyright © Garland Science 2014
Like your cell phone, cells receive signals from
the outside that bring about a behavioral response.
Fig. 16-2
Signals can act over long or short range.
Fig. 16-3
stress
Long Range Acting
neurotransmitter
hormone
fight or flight response
normal function also
Short Range Acting
shortest
The same signal can
induce different responses
in different cells.
non-ion
channel
receptor
sarcomere-like
Fig. 16-5
secretory vesicles
ion channel
receptor
sarcomere
Response depends on end target proteins present in each cell,
as well as which cell surface receptor is involved.
Cells integrate multiple signals to
induce a specific response.
Fig. 16-6
Responses can be fast or slow, depending on
whether transcription and translation are required.
Fig. 16-7
Signals are received by receptors, which can
act on the cell surface or intracellularly.
not membranepermeable
membrane-permeable
Fig. 16-7
Steroid hormones are
hydrophobic enough
to cross a plasma
membrane and bind
cytosolic nuclear
receptors.
Fig. 16-10
Steroid hormones are derived from cholesterol.
Fig. 16-9
polar modifications needed
to make more soluble
for function as endocrines
Blood vessel dilation involves
both membrane permeable and
non-permeable signals.
-Acetylcholine (non-permeable signal)
induces production of diffusible signal
(NO gas) from endothelial cells
-NO gas (permeable signal) induces
production of cGMP second messenger
in smooth muscle cells
Acetylcholine:
non-permeable
Nitric Oxide
NO:
permeable
Fig. 16-11
Cell-surface receptors relay the signal through
intracellular signaling molecules to final targets.
signal transduced
through chain reaction
of signal molecules
leading to final response
Fig. 16-12
Examples: kinases and G proteins
Common intracellular signaling proteins
Kinases
Fig. 16-15
G proteins
It must be possible for these to return to
ground state, so they can receive future signals.
Phosphatases return protein kinases
and their targets to ground state.
sometimes
dephosphorylation
turns protein ON
Fig. 16-15a
GTP hydrolysis returns G proteins to ground state.
Fig.16-15b
16-15a
Fig.
Monomeric G proteins are
assisted by GEFs and GAPs
Guanine nucleotide
Exchange Factor
activates
inactivates
GTPase-Activating
Protein
Fig. 16-16
Three Classes of
Membrane-Bound
Receptors
Fig. 16-17
Ion-Channel-Coupled Receptors
Responsible for depolarizing
post-synaptic membranes to threshold
fast and short range
Fig. 16-17a
Example: Acetylcholine Receptor in skeletal muscle
(Ch 4 and 17)
GPCR
G Protein-Coupled Receptor
Can Achieve Astonishing Speed and Sensitivity
largest family of cell surface receptor; > 800 types in humans
Fig. 16-17b
response to acetylcholine in cardiac pacemaker cells
Enzyme-Coupled Receptors
Responses typically slow, but highly sensitive.
Fig. 16-17c
Often a Kinase
GPCR
-contain seven
transmembrane α-helix
domains
-signal binding induces
conformational change
by shifting positions of
transmembrane domains
-activates G protein
Signaling molecule
depicted here: Adrenaline
Fig. 16-18
GPCR couples to G protein complex
Conformational change activates G protein complex
active G protein
switches effector
to “on” state
Fig. 16-19
G protein switches itself off through GTP hydrolysis
What would
happen if
GTP-hydrolysis
activity mutated?
Fig. 16-20
Locked in
Active State
Many Gα subunits activate enzymes
to produce 2nd messenger molecules
Fig. 16-22
cAMP is a common
second messenger
synthesized from ATP by
adenylyl cyclase enzyme
destroyed by hydrolysis
to AMP by cyclic AMP
phosphodiesterase enzyme
Fig. 16-23
G protein complexes can activate cAMP
production by Adenylyl Cyclase
GPCR and cAMP in Glycogen Breakdown
Gαs
Gαs:stimulates adenelyl cyclase
Gαi: inhibits adenylyl cyclase
“fight or flight” response
of skeletal muscle
PKA target:
phosphorylase kinase
Fig. 16-25
GPCR with adrenaline signal
in “fight or flight” response
epinephrine
Table 16-3
Adrenaline: synthesized from Tyrosine
Activated G protein complex directly stimulates
K+ channel opening in heart pacemaker cells
βγ
Fig. 16-21
K+ flow out
hyperpolarizes
cell membrane,
making harder
to activate
Cystic Fibrosis transporter (CFTR) and cAMP
regulate H2O efflux into respiratory & intestinal passages
thinning contents of passage
Cholera toxin locks Gα in active state
CFTR +/- : beneficial w/ cholera
CFTR -/- : Cystic Fibrosis
H 2O
Special Seminar
Ronald Breaker, Ph.D., Henry Ford II Professor of Molecular, Cellular, and
Developmental Biology and Professor of Molecular Biophysics and
Biochemistry, HHMI, Yale University
http://www.hhmi.org/scientists/ronald-r-breaker
Prospects for Bacterial Noncoding RNA Discovery
Date:
Time:
Place:
MONDAY, April 25, 2016
4:00 PM (refreshments at 3:45 PM)
116 TH Morgan Biology Building
Dr. Breaker discovered riboswitches and continues mechanistic and gene discovery studies
on RNA function in gene regulation and catalysis. Dr. Breaker is an HHMI investigator and
member of the National Academy of Sciences
GPCR pathways covered in previous class:
Gas /Adenylyl Cyclase-mediated:
-Adrenaline-stimulated glycogen breakdown in skeletal muscle
-opening of CFTR in endothelial cells lining respiratory & intestinal
passages
Gbg /K+ Channel-mediated:
-Acetylcholine-stimulated cardiac pace maker hyperpolarization
Today:
other Ga subtypes and Effector Enzymes:
-Light-stimulated visual response in rod cells (Gat /cGMP PDE)
-Acetylcholine-stimulated Ca2+ release in smooth muscle
contraction (Gaq /Phospholipase)
Rhodopsin is a light-activated GPCR
with cGMP second messenger
Gαt
PDE
light activates
cGMP destruction
cGMP PDE
negative response
allows more rapid
response to large
changes in light
Fig. 16-30 & 31
inhibiting neurotransmission
GPCR coupled to Gαq activates
phospholipase instead of adenylyl cyclase
DAG
activated G protein (Gq)
IP3
stimulates smooth
muscle contraction
Fig. 16-27
lipid cleavage products and Ca2+ act as second messengers
Enzyme-Coupled Receptors
Responses typically slow, but highly sensitive.
Fig. 16-17c
Many Enzyme-Coupled Receptors are
Receptor Tyrosine Kinases (RTKs)
auto-phosphorylation
Fig. 16-32
through phosphorylation
Most RTKs activate the
monomeric G protein, Ras
Fig. 16-33
Ras GOF mutations
in 30% human cancers!
cellular response
often cell growth
& proliferation
Activated Ras initiates phosphorylation cascade
amplifies signal
Fig. 16-34
Cyclin genes, etc.
Survival and growth signals
induce membrane localization of kinases
PH domain
PH domain
lipid phosphorylation
Insulin is survival/growth signal
Fig. 16-35
membrane localization of
PH domain kinases (Lab 4B)
Activated Akt inactivates pro-apoptotic Bad
and activates anti-apoptotic Bcl2
Fig. 16-36
Akt named after Ak mice
with thymus tumors
where it was discovered
Intrinsic signals can also induce apoptosis
in response to DNA damage.
Bax
Bcl2 sequesters
Bax to prevent
Bax channel
formation
(anti-apoptotic)
Bad sequesters Bcl2
to allow Bax channel
formation (pro-apoptotic)
Fig. 18-39
Activated Akt
also stimulates growth
through
nutrient/energysensing Tor kinase
Fig. 16-39
Insulin also stimulates GLUT4 membrane
recruitment for glucose uptake.
Akt
Animation
Karp CMB7
WELL FED
GLUCOSE
insulin
LAB 4B
PH-GFP (tGPH)
PO4
Akt InR GLUT4
PI3K
Acetylation of
TXN factors for
starvation genes
Low
NAD+
no glucose
STARVATION
Deacetylation
of TXN factors
by Sirtuins
TXN-ac
factors
inactive
Sirtuins
Active Insulin Signaling
PH-domain proteins:
membrane-localized
TXN
factors
High
NAD+
Active
Sirtuins
No Insulin Signaling
PH-domain proteins:
cytosolic and nuclear
RTK Mutations
Loss vs. Gain
of Function
Loss of Function: reduced response to signal
Y2 changed
to glutamic acid
wild type receptor
Gain of Function: response in absence of signal
Cells integrate multiple signals
into complex responses.
Fig. 16-43
Plants and animals evolved
signaling systems independently.
Plants use very different
processes.
Plants do not use RTKs,
steroid hormone nuclear
receptors, or cAMP, and
use few GPCRs.
They do use cell surface
Receptor Ser/Thr Kinases
(Ethylene Receptor).
Empty receptor activates kinase,
but inactivates gene expression.
Fig. 16-42