Samenvatting van het vak Cellular Signal Transduction (CST) uit de Bio-Farmaceutische Wetenschappen (BFW) minor (Computational Approaches to) Disease, Signaling and Drug Targets (DSDT).
Via GAP junctons it is possible to signal without a receptor. Small molecule scan transport to other
cells. Tumour cells have disturbed GAP junctons.
NF-κβ functons as a shutling method. NF-κβ transport in and out the cells, contnuously. This is
important for the transcripton of a set of genes.
Scafold proteins bring diferent signalling proteins together, so the proteins can wor together.
College 2 – GPCR signalling
The human genome consists of ~ 30.000 protein-coding genes. The druggable genome consists of ~
3.000 targets.
Cellular locatons of targets
Cell-surface receptors
Intercellular receptors
All cells receive and respond to signals from their surroundings, li e from another cell (direct)
or from signalling molecules (indirect).
Signalling molecules are secreted by one cell and bind to receptors expressed on other cells,
which ofen results in series of intracellular reactons.
Many intracellular signalling proteins functon as switches that are actvated by
phosphorylaton or GTP binding.
Proteins communicate by an actve and inactve state.
Current drug targets:
~ 800 GPCRs (~ 500 considered drug targets)
~ 25% of current drug target GPCRs
GPCRs signal from the outside of the cell all the way to the nucleus.
Examples of GPCR drugs:
Beta bloc ers
Drugs for migraine
Tastng of food and smelling perfume goes via GPCRs, but these are not interestng for drug
targetng.
The phylogenetc tree of GPCRs is based on sequence homology and the classifcaton of GPCRs is as
follows:
Class A: Rhodopsin-li e
Class B: Secretn-li e
Class C: Glutamate-li e
Adhesion-li e and Frizzled receptors
‘GRAFS’
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,GPCRs have 7 helices which go through the cell membrane. These helices form a barrel. Within these
receptors there is a orthostatc and allosteric ligand. Ligand binding to the allosteric or orthostatc
binding site van give the same efect, but could be diferent. Dependent on the allosteric binding site.
The class B GPCRs have a long N-terminal, which consists the orthostatc binding site. The N-terminal
is rigid and fxed.
Receptors have several chemical messengers:
Neurotransmiters
o Chemical released from nerve endings which travel across a nerve synapse to bind
with receptors on target cells, such as muscle cells or another nerve.
o Usually short lived and responsible for messages between individual cells.
Hormones
o Chemicals released from cells or glands and which travel some distance (mostly via
blood) to bind with receptors on target cells throughout the body.
o Hormones are used to communicate between (distant) organs and tssues. Therefore
they are more long lived.
Synthetc compounds (i.e. drugs)
Chemical messengers ‘switch on’ receptors without undergoing a reacton (unli e substrates for
enzymes).
Variety of natural ligands
Light
Catons
Small compounds
Peptdes
Proteins
GPCR signalling: The ligand binds to the receptor, which leads to an intracellular response (ofen) via
G protein. A ligand has a certain afnity to a receptor, which determines the degree of binding.
2
,Equilibrium state of bound and unbound ligand determines the afnity. The more bound ligand, the
higher the afnity.
The ligand has binding groups and the receptor has binding regions in its binding site. The binding
groups and binding regions are bound to each other with intermolecular bonds. As said, this actvates
the G protein. Via second messengers the gene regulaton is actvated and eventually, this gives a
cellular efect.
There are various types of G proteins:
Each G protein recognizes a partcular set of GPCRs
Each GPCR can recognize one or more G proteins
All G proteins have a similar structure and operate similarly. They have three subunits: alpha, beta
and gamma.
Gα-GDP is bound to a ‘silent’ receptor
Actvated receptor results in GDPGGTP exchange on G α
Gα is a GTPase regulatesGterminates G protein signalling
Small monomeric GTPases (e.g. Ras and Rho) are another class of signal proteins.
The G-protein is also a ligand of the GPCR. The GDP bound state of the G-protein has a higher afnity
for the receptor then the GTP bound state.
G protein (de-)actvaton cycle
The Gαs pathway Gαs protein-mediated actvaton of adenylyl cyclase causes formaton of the 2 nd
messenger cAMP. The cAMP-mediated actvaton of PKA causes actvaton of transcripton factors. A
rise in cAMP can alter gene transcripton.
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, The Gαi pathway only wor s when the receptor is actve.
Consttutve means that the receptor is actve without the presence
of the endogenous ligand.
Note: inhibiton of bac ground actvity due to constant levels of G i and Gs actvity overall efect
depends on dominant G protein, which is decided by which receptors are (consttutvely) actvated.
Gαq pathway:
Gq protein-mediated actvaton of plasma membrane-bound enzyme PLCβ causes formaton of 2 nd
messengers DAG and IP3. DAG actvated protein inase C, while IP 3 causes release of Ca2+ from
intracellular stores.
Ca2+-mediated actvaton of CaM- inase
causes actvaton of transcripton factors.
A rise of Ca2+ can alter gene transcripton.
By an overactve GPCR there is a desensitzaton mechanism.
Prolonged binding of agonist leads to C-term receptor phosphorylaton by Serine-Threonine
inases
This results in β-arrestn recruitment, which leads to receptor desensitzaton
There is also a sensitzaton mechanism when, for example, there is prolonged binding of antagonist.
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