Communication and Signalling Flashcards
What are the 3 basis of communication?
speed
mechanism
duration
Give two examples of contact-dependent signalling
Dropophila eye discs are regularly spaced as they differentiate and inhibit each other
Nerve cells
Give two examples of paracrine signalling
Mast cells releasing cytokines
Hedgehog (gene) expression stimulates Dpp
Give to examples of endocrine signalling
Pheromones can send signals to control hives
Adrenaline produces the “fight or flight” response
Give three actions of effectors
Alter metabolism
Alter gene expression
Alter cell shape or movement
Describe the morphogen gradient
Responses to signals are different depending on the concentration of morphogen. Cells commit to certain differentiations at different morphogen thresholds
What causes myeloproliferative neoplasms (bone marrow producing too many blood cells)
The JAK2 V617F mutation in the negative regulatory pseudokinase domain on JAK2
What causes chromic myeloid leukaemia?
BCR-Abi fusion protein causes sustained tyrosine kinase expression by Bcr enhancer/promotor
Compare the speeds of ion channel movement, changing protein levels via gene expression and phosphorylation
ion channels- fast
phosphorylation- quite fast
changing protein levels via gene expression- relatively slow
What are the major groups of eukaryotic kinases?
S/T kinases
Y (threonine) kinases
What is the receptor tyrosine kinase for epidermal growth factor (EGF)
Epidermal growth factor receptor (EGFR)
Describe the type I and II inhibitors of S/T kinases
Type I- binds the active conformation at an aspartate pointing to the ATP-binding pocket
Type II- binds inactive conformation
Describe type III and IV inhibitors of S/T kinases
Type III- binds to an allosteric pocket adjacent to the ATP binding pocket
Type IV- bind to an allosteric pocket away from the active site
What are the 4 main functions of receptors?
Recognise stimuli and transfer it into the cell
Amplify the cytoplasmic signal
Modulate effector systems
Adapt the system through feedback
How can the molecular nature of the signal transduction mechanism be predicted?
Not just the stimulus
Class/structure of the receptor
What sort of chemical mediators can hormones bind to?
Hormones
Neurotransmitters
Antibodies
Describe a general structure of ion channels
Transmembrane protein made of 2 or more α-helices crossing the lipid bilayer
2-6 subunits surrounding a pore
How are ion channel subgroups characterised?
Gating mechanism
Ion selectivity
What is a p-loop/pore?
Pocket where ion binds
Describe the structure of KcsA as a model for primordal channels
TMs are more more tightly packed on the cytoplasmic side, creating a gate
3 subunits: 2TM helices, 1 extracellular domain
Describe KvaP structure
S1-S4 TMs form a voltage sensing domain. S5 and S6 form the pore
Plugging mechanism stops ions entering
What are transient receptor potential (TRP) channels
Sense chemical and physical stimuli. e.g hot/spicy food
Common structural features with voltage-gated channels
Where does calmodulin bind on an ion channel?
The C-terminal cyclic nucleotide-binding domain
Describe the structure of ligand-gated ion channels
Gated
4 subunits
6 TM helices
P-loop
Cytoplasmic anchors
Describe the structure of transient receptor potential channels
Gated
4 subunits
6 TM helices
P-loop
Cytoplasmic anchors
Plugging mechanism
Describe the structure of voltage-gated ion channels
Gated
4 subunits
6-24 TM helices
P-loop
Cytoplasmic anchors
Voltage-sensing domains
Plugging
Describe the structure of simple channels
Not Gated
2 subunits
2 TM helices
P-loop
Describe ATP P2X structure
Trimeric
2 TM
ATP binding site in the extracellular domain
Describe glutamate receptor structure
Tetrameric - form as a dimer of dimers
Extracellular domain
3 TM and a half-helix
Similar structure to KcsA, except an inverted pore
Describe nicotinic receptor structure
Pentameric
4 TM
Extracellular domain recognising neurotransmitters
What neuronal nAChRs are important in nicotine addiction?
α4β2 are abundant in the cortex and hippocampus. These have a high affinity to nicotine and varenicline
What mutations are associated with tobacco dependence?
Polymorphisms in subunit genes CHRNA4 (α4) and CHRNA6 (α6)
What causes autosomal dominant nocturnal frontal lope epilepsy (ADNFLE)?
Mutations in the M2 domain (channel gate) of the human α4 neuronal subunit of the nicotinic acetylcholine receptor. This increases nicotinic-mediated transmission
What are the symptoms of ADNFLE?
Epilepsy which occurs during sleep. Delayed response in receptors. increased nicotinic-mediated transmission
What do AMPA receptors mediate?
Fast excitatory synaptic transmission in the CNS
What do NDMA receptors mediate?
Learning and memory. These are slower than other isoforms
What are kainate receptors linked to?
Schizophrenia, depression and huntington’s
Similar to AMPA
How does RNA splicing affect splicing isoforms?
Each subunit is encoded by a splicing isoform- flip/flop
Alternative splicing takes place in the primary transcripts
The isoforms have different kinetic properties- flop has faster desensitisation rate and reduced current responses to glutamate than flip
Why is RNA editing important in M2 (parasympathetic, in the heart) receptors?
Inside the channel pore is the GluA2 Q/R site. RNA editing converts Glu to Arg, blocking Ca2+ channel permeability
What happened to mice lacking RNA editing?
Prone to seizures and early death due to Ca2+ channel permeabilities not changing
What are NDMA receptors associated with?
Synaptic plasticity, learning and memory
How does ALS cause neurodegeneration?
The enzyme ADAR2 is downregulated, preventing GluA2 Q/R editing in motor neurons. Ca2+ permeability increases in AMPA receptors, damaging glutamate excitotoxicity
How does ALS cause neurodegeneration?
The enzyme ADAR2 is downregulated, preventing GluA2 Q/R editing in motor neurons. Ca2+ permeability increases in AMPA receptors, damaging glutamate excitotoxicity
What is decreased ADAR2 activity correlated with?
Cancer cells in glioblastoma
Ca2+ permeability increase in AMPA receptors
Describe P2X receptors
3 ATP gated to open the ion channel
3 subunits- 2 TM helices
Give three examples of P2X receptors targeted by drugs
P2X2- hearing loss
P2X4- pain
P2X7- inflammation
