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Summary Cell biology - BM10 - knowlegde test 1
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Cell biology - BM10 - knowlegde test 1
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Samenvatting cell biologySignal-Transduction Pathways
- 7-TMR -> G-protein coupled receptor
o 2% of the genome is coded for 7-
TMR
o 7 transmembrane receptor
o In youre nose and eye you have a
lot of 7-THR receptors
- cAMP and calcium are second messengers
o Associated with GPCR
- receptor tyrosine kinases
- RTK – ras mapK
Intracellular signalling proteins
- Upstream and downstream
- Enzymes
- Upstream ->ligand
- Downstream -> signal
Specificity
- Signal molecule fits binding site on its completing receptor, other signals do
not fit
- Each GPCR has a specifity to ligands
- Model and find the right first messenger
Amplification
- When enzymes activate enzymes, the number of affected
molecules increases geometrically in an enzyme cascade
- 1 ligand that can release the response
o That can be a couple enzymes
Modularity
- Proteins with multivalent affinities form diverse signalling complexes from
interchangeable parts.
- Phosphorylation provides reversible points of interaction
- The different molecules fit into eachother
,Desensitization/ adaption
- Receptors activation triggers a feedback circuit that shuts off the receptor
or removes it from the cell surface
- Receptor activates trigger
Integration
- When two signals have opposite effect on a metabolic characteristic sush as
the concentration of a second messenger X of the membrane potential Vm,
the regulatory outcome results from the intergraded input from both
receptors
- Effect and response
- Battle between the ligands
Extracellular signal molecule
- Receptor protein
o On the plasma membrane of the target
- Extra cellular signalling proteins
- Effector proteins
o Lead to different pathways
o Metabolic enzyme ->altered metabolism
o Transcription regulatory protein -> altered gene
expression
o Cytoskeletal protein -> altered cell shape or movement
Relay of a signal is mostly done via phosphorylation and GTP
- Phosphorylation with protein kinases
o Proteins activated
o Specific kinases
- Phosphorates
o Remove protein
o Protein is deactivated
- GTP
o GTP activates and GDP exchange
o When D is removed and the T is
added the protein is on
o G proteins because they bind GTP
o With the help of GEFs and GAPs
- Second messengers: Calcium/DAG/cAMP/
ubiquitinylation
,Cell signalling pathways
- Contact dependent -> inflammation
- Paracrien
- Synaptic -> normal axon dendrite signalling
- Endocrine -> GPCR
o Finds it way to the target cell
- Paracrine, synaptic and endocrine signaling share
signalling molecules but differ in speed and
selectivity.
The three major classes of cell-surface receptors
- Ion channel coupled receptor
- G- protein coupled receptor
- Enzyme couples receptor
Summary
- G protein-coupled receptors (GPCRs) are the most intensively
studied drug targets, mostly due to their substantial
involvement in human pathophysiology and their
pharmacological tractability.
- 475 drugs (~34% of all drugs approved by the US Food and Drug Administration (FDA)) act at
108 unique GPCRs.
- Approximately 321 agents are currently in clinical trials, of which ~20% target 66 potentially
novel GPCR targets without an approved drug.
- The major disease indications for GPCR modulators show a shift towards diabetes, obesity
and Alzheimer disease, although several central nervous system disorders are also highly
represented.
How many GPCRs do we have?
- Estimates of the number of GPCRs in the human genome vary widely. Based on their
sequences, as well as on their known or suspected functions, there are estimated to be five
or six major classes of GPCR.
- More than 800 GPCRs were listed.
- There are approximately 460 type A olfactory receptors, although estimates range from 322-
900. This large number of olfactory receptors accounts for the ability of humans to detect a
wide variety of exogenous (olfactory) ligands.
- 367 human endoGPCRs and 392 mouse endoGPCRs have been identified. The term
endoGPCR refers to GPCRs for endogenous (non-olfactory) ligands.
- n view of the known existence of alternatively spliced variants and editing isoforms of GPCRs,
it is likely that the true number of GPCRs will never be known and is much higher than
estimated!
, G- protein coupled receptor
- Recognises a G- protein
o Needs to be activated
o GTP
- By activation of the G-protein the second messengers
come
- A G-protein consist of a α, β and γ subunit
o Heterotrimeric G-proteins -> 80kD
o Monomeric G-proteins -> 20kD
Small proteins
20kD about 180 amino acids
- Α subunit will part and β and γ subunit stay together
o All have a different function
- G protein families
o S and I always bind cAMP
o 12 has a function with rho
Crossover GPCR signalling and rho
Basis of signalling through GPCR
- First the ligand binds
- Than the G-protein will bind
- The GTP GDP switch occurs
- The β and γ subunit will separate from the α subunit
The GPCR route toward cAMP production and activation of the transcription regulatory protein
CREB
1. Binding of ligand to GPCR
2. Activation of G-protein Gs
3. Activation of adenylyl cyclase
4. Production of cAMP
5. Activation of PKA
6. Transfer of PKA to cell nucleus
7. Activation CRE-binding protein (CREB) – transcriptional regulators
8. Binding of CREB to cyclic AMP response element (CRE)
9. Gene transcription
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