cell-surface receptors Flashcards
1
Q
types
A
- GPCR
- ion channel-linked receptor
- enzyme linked receptor (TKR)
2
Q
g-protein coupled receptor
A
- Participate in processes responsible for vision, smell, taste and neuronal transmission in response to photons or binding of ions, hormones, peptides, chemokines and other factors.
- GPRs are molecular targets for many of currently used drugs 30% of commercially available drugs have GPRs as target.
- GPRs share a common seven-transmembrane α-helical bundle structure but can accommodate thousands of different ligands.
- Large amount of receptor diversity, but common mechanism of action
- Transmit signals to intracellular targets via G proteins
- Targets are plasma membrane (PM) bound enzymes or ion channels
3
Q
GPCR - general mechanism of action
A
- Binding of ligand to extracellular domain of GPRs induces conformational change that allows cytosolic domain of the receptor to bind to inactive G protein at inner face of PM.
- This interaction activates the G protein, which dissociates from the receptor
- Activated G protein alfa subunit can now bind GTP instead of GDP, causing dissociation into activated alfa vs. beta/gamma subunits. Each of these can go on to activate target proteins.
4
Q
alfa-subunit
A
- a monomeric GTPase
- is active when bound to GTP which happens after a ligand binds to teh GPCR and a GEF (guanine nucleotide exchange factor) changes the GDP for GTP
- is inactive when bound to GDP which happens after GTP is hydrolysed by a GAP (GTPase activating protein)
5
Q
Gs - mechanism
A
- binding of ligand to GPCR
- activation of Gs protein subunits
- alfa-unit activates adenylyl cyclase
- ATP –> cAMP
- cAMP activates PKA
- PKA activates CREB
- CREB binds CBP and causes transcription of CREB-binding element containing genes
6
Q
Gi - mechanism
A
- opposite of Gs –> deactivates adenylyl cyclase
- so: no cAMP, no active PKA, no active CREB, no transcription of target genes
7
Q
Gq - mechansim
A
- binding of ligand to GPCR
- activation of Gq protein subunits
- alfa-unit activates phospholipase C-beta
- PIP2 –> IP3 and diacylglycerol
- IP3 opens IP3-gated calcium channels on ER
- calcium together with diacylglycerol activate PKC
- PKC has many effects
- the calcium also activates calmodulin which activates CaM kinase which has many effects too
8
Q
enzyme-linked receptors
A
- Tyrosine kinase-linked receptors (TKRs):
• Cell surface receptors that are directly linked to intracellular enzymes (kinases).
• Includes receptors for most growth factors (NGF, EGF, PDGF), insulin, and Src.
• Common structure: N terminal extracellular ligand-binding domain, single TM domain, cytosolic C-terminal domain with tyrosine kinase activity. - Proteins that interact with the TKRs need to have SH2 or SH3 domains
- Src homology 2 (SH2) domains on other proteins bind to phosphotyrosine containing regions of TKRs resulting in:
• localization of SH2-containing proteins at plasma membrane.
• association of SH2-containing proteins with other proteins.
• phosphorylation of SH2-containing proteins.
• activation of enzymatic activity of SH2-containing proteins.
9
Q
TKR activation
A
- ligand binding induces receptor dimerization (receptor crosslinking).
- dimerization leads to autophosphorylation of the receptor (cross phosphorylation).
- phosphorylation increases kinase activity & also creates specific new binding sites.
- proteins that bind to these new binding sites transmit intracellular signals.
10
Q
RAS signalling
A
- Activated TRK activates RAS GEF(GTPase)
- This GEF activates Ras by exchanging its GDP with GTP
- Ras –> MAP kinase kinase kinase (Raf)
- Raf –> MAP kinase kinase (Mek) via phosphorylation
- Mek –> MAP kinase (Erk)
- Erk has many downstream targets
11
Q
PI3K signalling
A
- survival signal binds to TKR
- activated TKR activates PI3K
- PIP2 –> PIP3 (phosphorylation)
- PIP3 activates Akt and PDK1 (PDK1 also activates Akt)
- Akt causes increased growth and apoptosis/autophagy inhibition
