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Cell Signaling (BIO-203)
Lecture 4
How the signaling terminates
The Gα-GTP state is short-lived because the
bound GTP is hydrolyzed to GDP in minutes.
 The GPCR signal-transduction system
contains a built-in feedback mechanism that
ensures the effector protein becomes
activated only for a few seconds or minutes
following receptor activation.
 Gα the switches back to Gα-GDP state
blocking any further activation of effector
proteins.
 The resulting Gα-GDP reassociates with Gβγ
and the complex becomes ready to interact
with an activated receptor to stop the
process.
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Light activates Gαt- Coupled
rhodopsins
Human retina contains 2 types of
photoreceptor cells:
 Rods stimulated by moonlight over a range
of wavelengths.
 Cones involved in color vision.
 They are the primary recipients of visual
stimulation.
 Rhodopsin consists of the protein opsin
which has a usual GPCR structure covalently
bonded to light-absorbing pigment 11-cisretinal.

The trimeric G Protein
couple to rhodopsin is
called transducin (Gt).
 It contains Gαt subunit.
 Rhodopsin and Gαt
subunit are found only in
rod cells.
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Rhodopsin is sensitive enough
to respond to a single photon
of light, this response takes
place in the form of
isomeriztion,
Therefore, when a photon of
light enters the eye, it is
absorbed by the retinal and
causes a change in its
configuration
from 11-cis retinal to all-trans
retinal.
This isomeriztion induces
conformational changes in
Rhodopsin that activates the
G-protein.
Isomerization
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is the process by which one molecule is
transformed into another molecule which
has exactly the same atoms, but the
atoms are rearranged e.g. A-B-C → B-AC.
Light activated rhodopsin pathway
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In dark adopted rod cells:
Light absorption generated activated opsin
Opsin binds inactive GDP-bound Gαt protein and
mediates replacement of GDP with GTP
The free Gαt-GTP activates cGMP
phosphodiesterase (PDE) by binding to its inhibitory
γ subunits and dissociating them from the catalytic α
and β subunits.
The free α and β subunits convert cGMP to GMP.
The resulting decrease in cGMP leads to dissociation
of cGMP from the nucleotide-gated channels in the
plasma membrane and closing of channels.
The membrane then becomes hyperpolarized.
Light activated rhodopsin pathway
GPCRs that activate adenylyl clase
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Following ligand binding to the receptor, the
Gs protein relays the hormone signal to the
effector protein,, adenylyl cyclase.
Gs cycles between an inactive form with bound
GDP and an active form with bound GTP.
Dissociation of the active form yields the Gsα ·
GTP complex, which directly activates adenylyl
cyclase. Activation is short-lived because GTP
is rapidly hydrolyzed (step 5 ).
This terminates the hormone signal and leads
to reassembly of the inactive Gs · GDP form,
returning the system to the resting state.
Binding of another hormone molecule causes
repetition of the cycle. Both the Gγ and
Gsα subunits are linked to the membrane by
covalent attachment to lipids.
Binding of the activated receptor to
Gsα promotes dissociation of GDP and its
replacement with GTP.
GPCRs that activate and inhibit adenylyl cyclase
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In the liver, glucagon and epinephrine bind to different GPCRs, but
binding of both hormones activates adenylyl cyclase and thus
triggers the same metabolic responses. Both types of receptors
interact with and activate Gs, converting the inactive Gs · GDP
to the active Gsα · GTP form. Activation of adenylyl cyclase,
and thus the cAMP level, is proportional to the total
concentration of Gsα · GTP resulting from binding of both
hormones to their respective receptors.
In some cells, the cAMP level can be both up-regulated and
down-regulated by the action of different hormones.
Prostaglandin PGE1 and adenosine inhibit the enzyme. The
receptors for PGE1 and adenosine interact with inhibitory Gi,
which contains the same β and γ subunits as stimulatory Gs but
a different α subunit (Giα).
In response to binding of an inhibitory ligand to its receptor,
the associated Gi protein releases its bound GDP and binds
GTP; the active Giα · GTP complex then dissociates from
Gβγ and inhibits (rather than stimulates) adenylyl cyclase.
GPCRs that activate and inhibit adenylyl cyclase