Cell Signaling and

Regulation of
Metabolism
bjectives
Different steps in signaling pathways
The second messenger systems
Function of signaling pathways for
Signal transmission
Amplification
The role of signaling pathways in
regulation and integration of metabolism
Cell Cell- -to to- -cell communication cell communication
s absolutely essential for multicellular s absolutely essential for multicellular
organisms organisms
External signals are converted into External signals are converted into
responses within the cell responses within the cell
Signal transduction pathways Signal transduction pathways
Convert signals on a cell's surface into cellular Convert signals on a cell's surface into cellular
responses responses
nimal and plant cells nimal and plant cells
Have cell junctions that directly connect the Have cell junctions that directly connect the
cytoplasm of adjacent cells cytoplasm of adjacent cells
Plasma membranes
Plasmodesmata
between plant cells
Gap junctions
between animal cells
Figure 11.3 (a) CeII junctions. oth animals and plants have cell junctions that allow molecules
to pass readily between adjacent cells without crossing plasma membranes.
Figure 11.3 (b) CeII-ceII recognition. %wo cells in an animal may communicate by interaction
between molecules protruding from their surfaces.
n local signaling, animal cells n local signaling, animal cells
May communicate via direct contact May communicate via direct contact
n other cases, animal cells n other cases, animal cells
Communicate using local regulators Communicate using local regulators
(a) Paracrine signaIing. secreting cell acts
on nearby target cells by discharging
molecules of a local regulator (a growth
factor, for example) into the extracellular
fluid.
(b) Synaptic signaIing. nerve cell
releases neurotransmitter molecules
into a synapse, stimulating the
target cell.
Local regulator
diffuses through
extracellular fluid
%arget cell
Secretory
vesicle
Electrical signal
along nerve cell
triggers release of
neurotransmitter
Neurotransmitter
diffuses across
synapse
%arget cell
is stimulated
Local signaling
n long n long- -distance signaling : distance signaling :
Hormones Hormones
neurotransmitters neurotransmitters
Hormone travels
in bloodstream
to target cells
(c) HormonaI signaIing. Specialized
endocrine cells secrete hormones
into body fluids, often the blood.
Hormones may reach virtually all
body cells.
ong-distance signaling
lood
vessel
%arget
cell
Endocrine cell
%e %ree Stages of CeII %e %ree Stages of CeII
SignaIing: SignaIing: !70;0 !70;0
EX%#CELLUL#
LUD
#eceptor
Signal
molecule
#elay molecules in a signal transduction pathway
Plasma membrane
CY%PLSM
ctivation
of cellular
response
Figure 11.5
Reception 1 %ransduction 2 Response 3
Reception: Reception:
signal molecule binds to a receptor signal molecule binds to a receptor
protein, causing it to change shape protein, causing it to change shape
%e binding between signaI moIecuIe %e binding between signaI moIecuIe
(Iigand) (Iigand)
And receptor is And receptor is highly specific highly specific
ach cell has a ach cell has a specific specific set of receptors set of receptors
A conIormational change in a receptor A conIormational change in a receptor
Is oIten the initial transduction oI the signal Is oIten the initial transduction oI the signal
%here are three main types oI %here are three main types oI
membrane receptors membrane receptors
G G- -protein protein- -linked linked
%yrosine kinases %yrosine kinases
Ion channel Ion channel
%ransduction %ransduction
oo Change of external signal into intracellular Change of external signal into intracellular
message with message with amplification amplification and and formation formation of of
second messenger second messenger
oo Cascades of molecular interactions relay Cascades of molecular interactions relay
signals from receptors to target molecules in signals from receptors to target molecules in
the cell the cell
oo Multistep pathways Multistep pathways
oo Can amplify a signal Can amplify a signal
oo Provide more opportunities for coordination and Provide more opportunities for coordination and
regulation regulation
Response Response
Cell signaling leads to regulation of Cell signaling leads to regulation of
cytoplasmic activities or transcription cytoplasmic activities or transcription
D|fferent kesponses to the Same S|gna||ng Mo|ecu|e
(A) D|fferent Ce||s
Different Responses to the Same Signaling Molecule
(B) ne Cell but, Different Pathways
pog|cem|a
G|ucagon secret|on
epatocte G|ucagon]receptor b|nd|ng
Second messenger cAM
kesponse Lnzme phosphor|at|on
G|cogen snthase
(Inact|ve form)
Inh|b|t|on of g|cogenes|s
G|cogen phosphor|ase
(Act|ve form)
St|mu|at|on of g|cogeno|s|s

Small Molecules and ons as Small Molecules and ons as
Second Messengers Second Messengers
%he extracellular %he extracellular signal molecule signal molecule ( (Iigand Iigand) )
that binds to the receptor is a pathway's that binds to the receptor is a pathway's
" "first messenger first messenger. .
Second messengers Second messengers are small, nonprotein, are small, nonprotein,
water water- -soluble molecules or ions soluble molecules or ions that spread that spread
throughout a cell by diffusion. throughout a cell by diffusion.
%wo important second messenger
systems:
AdenyIyI cycIase system
CaIcium/pospatidyIinositoI system
opyright 2008 Pearson Education, Inc., publishing as Pearson Benjamin ummings
%here are three main types oI %here are three main types oI
membrane receptors membrane receptors
G G- -protein protein- -linked linked
%yrosine kinases %yrosine kinases
Ion channel Ion channel
G-Protein-Coupled #eceptor (GPC#)
r G Protein-linked #eceptor
7 transmembrane domains
Adenylyl Cyclase System
-proteins are heterotrimeric, with 3 subunits -,
., .
A G-protein that activates cyclic-AMP Iormation
within a cell is called a stimulatory -protein,
designated
s
with alpha subunit
s-
.

s
is activated, e.g., by receptors Ior the hormones
epinephrine (.-adrenergic receptor) and glucagon
ALSO toxins e.g., Cholera(+) and Bordetella pertussis toxins(-)
Adenylate Cyclase (A is a transmembrane protein, with
cytosolic domains Iorming the catalytic site. %oxins e.g.,
CoIera(+) and BordeteIIa pertussis toxins(-).
A
hormone
signal

outside

GP# plasma
membrane




G%P GDP A%P cAMP PP
i

-- cytosol
GDP ..G%P
%he %he sequence of events sequence of events by which a hormone by which a hormone
activates cMP signaling: activates cMP signaling:
1. nitially 1. nitially GG
--
has bound has bound GDP GDP, and , and -- ..
subunits subunits are complexed together. are complexed together.
GG
..,,
,, the complex of the complex of .. subunits, subunits, inibits G inibits G
--
..
A
hormone
signal

outside

GP# plasma
membrane




G%P GDP A%P cAMP PP
i

-- cytosol
GDP ..G%P
. . Hormone binding Hormone binding, causes a , causes a conformationaI conformationaI
cange cange in the receptor that is transmitted to a in the receptor that is transmitted to a GG- -
protein protein
GG
--
releases GDP binds G%P ( releases GDP binds G%P (GDP GDP- -G%P excange G%P excange). ).
A
hormone
signal

outside

GP# plasma
membrane




G%P GDP A%P cAMP PP
i

-- cytosol
GDP ..G%P
. . Substitution of Substitution of G%P G%P for GDP causes another for GDP causes another
conformational change in conformational change in GG
--
..
GG
--
- -G%P G%P dissociates from the inhibitory dissociates from the inhibitory . . complex complex
can now bind to and activate denylate Cyclase. can now bind to and activate denylate Cyclase.
A
hormone
signal

outside

GP# plasma
membrane




G%P GDP A%P cAMP PP
i

-- cytosol
GDP ..G%P
. . AdenyIate CycIase AdenyIate CycIase, activated by the stimulatory , activated by the stimulatory
GG
--
- -G%P, catalyzes synthesis of G%P, catalyzes synthesis of cAMP cAMP..
A
hormone
signal

outside

GP# plasma
membrane




G%P GDP A%P cAMP PP
i

-- cytosol
GDP ..G%P
Adenylyl Cyclase Adenylyl Cyclase
System: System:
cAMP cAMP- -Dependent Dependent
Protein Kinase Protein Kinase
(Protein Kinase A) (Protein Kinase A)
. . Protein Kinase A Protein Kinase A
(cMP Dependent Protein (cMP Dependent Protein
Kinase) affection Kinase) affection
Signal Amplification Signal Amplification
is an important feature of signal cascades: is an important feature of signal cascades:
ne hormone molecule can lead to formation of ne hormone molecule can lead to formation of
many cMP molecules. many cMP molecules.
Each catalytic subunit of Protein Kinase Each catalytic subunit of Protein Kinase
catalyzes phosphorylation of many proteins catalyzes phosphorylation of many proteins
during the life during the life- -time of the cMP. time of the cMP.
Signal Signal Amplification Amplification ( (Cascade Cascade) )
Phosphorylation Phosphorylation Cascade Cascade
pinephrine pinephrine lycogen Breakdown lycogen Breakdown
1. 1.
--
hydrolyzes G%P to hydrolyzes G%P to GDP P GDP P
ii
. ( . (TPase TPase. .
%he presence oI %he presence oI DP DP on G on G
aa
causes it to rebind to causes it to rebind to
the inhibitory the inhibitory . . complex. complex.
Adenylate yclase is no longer activated. Adenylate yclase is no longer activated.
2. 2. Phosphodiesterases Phosphodiesterases catalyze hydrolysis oI catalyze hydrolysis oI
cAMP cAMP AMP AMP..
. . Protein Phosphatase Protein Phosphatase catalyzes removal by hydrolysis oI catalyzes removal by hydrolysis oI
phosphates that were attached to proteins via Protein Kinase A. phosphates that were attached to proteins via Protein Kinase A.
4. 4. Absence Absence of hormone bound to the of hormone bound to the
receptor receptor
Turn off of the signal: Turn off of the signal:
phosphod|esterase*
AMP
Calcium Ions/Phosphotidyl Calcium Ions/Phosphotidyl
inositol System inositol System
PospoIipase PospoIipase
C C
DA DA
IP IP

Inositol %riphosphate 2 Inositol %riphosphate 2
nd nd
Messenger Messenger
angiotensin II , , ADH , H
lycogen synthesis and breakdown are lycogen synthesis and breakdown are
reciprocally regulated reciprocally regulated
Redinactive forms, green active forms.
Inactive Inactive
Active Active
Cell signaling allows
WSignal transmission and amplification
WRegulation of metabolism
WIntercellular communications &
coordination of complex biologic functions
Take Home Message Message
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