Essential Cell Biology FOURTH EDITION
Transcript Essential Cell Biology FOURTH EDITION
Alberts • Bray • Hopkin • Johnson • Lewis • Raff • Roberts • Walter
Copyright © Garland Science 2014
Like your cell phone, cells receive signals from
the outside that bring about a behavioral response.
Signals can act over long or short range.
Long Range Acting
fight or flight response
normal function also
Short Range Acting
The same signal can
induce different responses
in different cells.
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.
Responses can be fast or slow, depending on
whether transcription and translation are required.
Signals are received by receptors, which can
act on the cell surface or intracellularly.
Steroid hormones are
to cross a plasma
membrane and bind
Steroid hormones are derived from cholesterol.
polar modifications needed
to make more soluble
for function as endocrines
Blood vessel dilation involves
both membrane permeable and
-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
Cell-surface receptors relay the signal through
intracellular signaling molecules to final targets.
through chain reaction
of signal molecules
leading to final response
Examples: kinases and G proteins
Common intracellular signaling 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.
turns protein ON
GTP hydrolysis returns G proteins to ground state.
Monomeric G proteins are
assisted by GEFs and GAPs
Three Classes of
Responsible for depolarizing
post-synaptic membranes to threshold
fast and short range
Example: Acetylcholine Receptor in skeletal muscle
(Ch 4 and 17)
G Protein-Coupled Receptor
Can Achieve Astonishing Speed and Sensitivity
largest family of cell surface receptor; > 800 types in humans
response to acetylcholine in cardiac pacemaker cells
Responses typically slow, but highly sensitive.
Often a Kinase
-signal binding induces
by shifting positions of
-activates G protein
depicted here: Adrenaline
GPCR couples to G protein complex
Conformational change activates G protein complex
active G protein
to “on” state
G protein switches itself off through GTP hydrolysis
Many Gα subunits activate enzymes
to produce 2nd messenger molecules
cAMP is a common
synthesized from ATP by
adenylyl cyclase enzyme
destroyed by hydrolysis
to AMP by cyclic AMP
G protein complexes can activate cAMP
production by Adenylyl Cyclase
GPCR and cAMP in Glycogen Breakdown
Gαs:stimulates adenelyl cyclase
Gαi: inhibits adenylyl cyclase
“fight or flight” response
of skeletal muscle
GPCR with adrenaline signal
in “fight or flight” response
Adrenaline: synthesized from Tyrosine
Activated G protein complex directly stimulates
K+ channel opening in heart pacemaker cells
K+ flow out
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
Ronald Breaker, Ph.D., Henry Ford II Professor of Molecular, Cellular, and
Developmental Biology and Professor of Molecular Biophysics and
Biochemistry, HHMI, Yale University
Prospects for Bacterial Noncoding RNA Discovery
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
Gbg /K+ Channel-mediated:
-Acetylcholine-stimulated cardiac pace maker hyperpolarization
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
allows more rapid
response to large
changes in light
Fig. 16-30 & 31
GPCR coupled to Gαq activates
phospholipase instead of adenylyl cyclase
activated G protein (Gq)
lipid cleavage products and Ca2+ act as second messengers
Responses typically slow, but highly sensitive.
Many Enzyme-Coupled Receptors are
Receptor Tyrosine Kinases (RTKs)
Most RTKs activate the
monomeric G protein, Ras
Ras GOF mutations
in 30% human cancers!
often cell growth
Activated Ras initiates phosphorylation cascade
Cyclin genes, etc.
Survival and growth signals
induce membrane localization of kinases
Insulin is survival/growth signal
membrane localization of
PH domain kinases (Lab 4B)
Activated Akt inactivates pro-apoptotic Bad
and activates anti-apoptotic Bcl2
Akt named after Ak mice
with thymus tumors
where it was discovered
Intrinsic signals can also induce apoptosis
in response to DNA damage.
Bax to prevent
Bad sequesters Bcl2
to allow Bax channel
also stimulates growth
nutrient/energysensing Tor kinase
Insulin also stimulates GLUT4 membrane
recruitment for glucose uptake.
Akt InR GLUT4
TXN factors for
of TXN factors
Active Insulin Signaling
No Insulin Signaling
cytosolic and nuclear
Loss vs. Gain
Loss of Function: reduced response to signal
to glutamic acid
wild type receptor
Gain of Function: response in absence of signal
Cells integrate multiple signals
into complex responses.
Plants and animals evolved
signaling systems independently.
Plants use very different
Plants do not use RTKs,
steroid hormone nuclear
receptors, or cAMP, and
use few GPCRs.
They do use cell surface
Receptor Ser/Thr Kinases
Empty receptor activates kinase,
but inactivates gene expression.