Molecular Pharmacology 2

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  • Created by: Lydia
  • Created on: 23-04-18 15:50
What was diazepam first marketed as?
Valium
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Are the genomic or non-genomic onset of the effects of steroids rapid (seconds/minutes)?
Non-genomic
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What happens when progesterone metabolites are added to water with fish in it?
The fish are rapidly anaethetised
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What are the effects of alphaxalone?
Anaesthetic
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In what manner do neurosteroids act on GABAaRs?
Non-genomic
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What happens to GABA maximal response when the concentration of neurosteroid 5a3a is increased?
There is a higher maximal response from GABA
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Neurosteroids are what type of modulators of GABAaRs?
Positive allosteric modulators
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What situations would lead to an increase of 5a3a?
Pregnancy, stress, antidepressants and alcohol
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Do GABAaRs have a high or low affinity for GABA?
Low
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What is phasic inhibition?
High conc of GABA in the synapse for short amount of time, with GABAaRs opening to allow Cl- into the post synaptic cell, inhibiting depolarisation
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What is tonic inhibition?
Low conc of GABA outside of the synapse opens extrasynapic GABAaRs allowing Cl- into cells with these receptors
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What is the benefit of tonic inhibition?
Acts as a feedback loop to reduce stress response
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What does CRH stand for?
Corticotropin-releasing hormone
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What does PVN (hypothalamus) stand for?
Paraventricular nucleus
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What is released when a neuron in the PVN is stimulated?
Corticotropin-releasing hormone, then ACTH and finally glucocorticoids
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What happens to the release of CRH from the PVN at high concentrations of 5a3a neurosteroid?
Reduction of CRH release
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What does CRH control?
The stress response
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What is CRH also known as?
Corticotropin-releasing factor (CRF)
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How do early life stress events prevent neurosteroid inhibition?
Increase CRH expression in PVN, which increases glutamate release and this blocks the GABA inhibition
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What type of cells are involved in glutamate clearance from the synapse/ extrasynaptic space?
Glial cells
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After birth, what happens to the sensitisation of GABAaRs to neurosteroids?
GABAaRs become desensitised to neurosteroids
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What are the effects of desensitisation of neurosteroids post partum?
Increase neuronal firing, leads to increase oxytocin, leads to uterine contraction and lactation
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How is neurosteroid sensitivity on GABAaRs regulated?
Phosphorylation
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If GABAaR is phosphorylated, is it sensitive or insensitive to neurosteroids?
Sensitive
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What kinase phosphorylates GABAaR in order to increase neurosteroid sensitivity?
PKC
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Post partum, are GABAaRs phosphorylated?
No, they are dephosphorylated by phosphatases
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How many subunits form a GABAaR?
5
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How many alpha helices are in each subunit of a GABAaR?
4
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What is etomidate?
General anaesthetic
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What GABAaR subunit does etomidate need to be present for it to work?
Beta-2
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What are the effects of low dose etomidate on beta2 N265S mutant mice?
Nothing- they are not sedated
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What are the effects of neurosteroid enhancement of GABA by the Q241W mutated alpha 1 GABAaR subunit?
Ablated effects of GABA enhancement- no positive allosteric effects of neurosteroids
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What phenotype does a alpha2 Q241W mutant mouse have?
Anxiogenic
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During post-natal development in mice, what happens to alpha2 subunits of GABAaRs in the ventrobasal nucleus of the thalamus?
They become alpha1 subunits
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What happens to GABAaR-mediated phasic inhibition during post-natal development?
It is reduced- less phasic inhibition after development
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How does finasteride effect 5a3a?
Inhibits 5a3a production by preventing 5a-DHP (a 5a3a progenitor) to be formed
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At postnatal day 7 of a mouse, what are the effects of neurosteroids on mIPSCs on ventrobasal neurons?
Neurosteroids act as positive allosteric modulators on GABAaRs, so a prolonged mIPSC
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How is gamma-cyclodextrin used as a tool to study neurosteroids?
Gamma-cyclodextrin sequester the effects of neurosteroids
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What drug prevents the effects of 5a-DHP on enhanced synaptic inhibition?
Indomethacin
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Does the effect of neurosteroids dissipate in development before or after the transition of alpha-2 to alpha-1 GABAaR subunits?
Before alpha-2 subunits transition to alpha-1
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What are the effects of NMDA activation on neurosteroid synthesis in the hippocampus?
NMDA activation leads to increased neurosteroid synthesis in the hippocampus
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What are the effects of alcohol on neurosteroid synthesis?
Enhanced neurosteroid synthesis
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What are the effects of prozac on neurosteroid synthesis?
Enhanced neurosteroid synthesis
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What family of receptors are GABAaRs a member of?
Cys-loop
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Which alpha subunits of a GABAaR are involved in phasic inhibition?
Alpha 1, 2, 3
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Which alpha subunits of a GABAaR are involved in tonic inhibition?
Alpha 5
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How many different subunits are there of GABAaRs?
19
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What family of drugs is chlordiazepoxide a member of?
Benzodiazepene
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Which is more potent, chlordiazepoxide or diazepam?
Diazepam
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What are the positive effects of classical benzodiazepenes?
Anxiolytic, anticonvulsant and myorelaxant
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What are the negative effects of classical benzodiazepenes?
Sedating, interact with alcohol, impair memory, induce tolerance/ dependence, potential for abuse
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Which alpha subunits do benzodiazepenes interact with?
1, 2, 3, 5
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What % of GABAaRs are affected by benzodiazepenes?
75%
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What type of modulator are benzodiazepenes on GABAaRs?
Positive allosteric modulator
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How do benzodiazepenes affect the maximal efficacy of GABAaRs?
They do not alter the maximal efficacy
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How do benzodiazepenes affect the affinity of GABA to GABAaRs?
Increased affinity of GABA to the orthosteric site
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How does diazepam increase the affinity of GABA to the GABAaRs?
It increases the frequency of the GABAaR channel opening
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Which GABAaR subunit is involved in sedation?
Alpha-1
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Which GABAaR subunit is involved in cognition?
Alpha-5
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Which GABAaR subunits are involved in anxiety?
Alpha-2/3
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A negative allosteric modulator to enhance cognition should be selective for which GABAaR subunit?
Alpha-5
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A positive allosteric modulator to reduce anxiety without causing sedation should be selective for which GABAaR subunits?
Alpha-2/3
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What is the predominant subtype of GABAaRs in the central nucleus of the amygdala?
alpha-2 containing
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TPA023 has selectivity to increase the efficacy of which GABAaR subunits?
Alpha 2/3
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What are the effects of knocking out alpha-5 subunit in mice doing the morris water maze task?
They learn faster and can complete the task quickly with fewer practices
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What does the drug amiloride target?
ENaC channels
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What is reverse pharmacology?
Find a pharmalogical tool and THEN find the disease phenotype associated with it
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How much money does the clinical phase of drug trials cost ($)?
$1.5 billion
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How much does the pre-clinical phase of drug trials cost ($)?
$1 billion
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What is the gene that is mutated in Muckle-Wells Syndrome?
CIAS1 (Cryopyrin, which encodes NLRP3 and regulated the inflammatory response)
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What are the symptoms of Muckle-Wells Syndrome?
A rash, fever, hearing loss and kidney failure
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What are cultured primary cells?
Cells that come straight from in vivo that are only expanded a small number of times in order to keep relevant biological complexity
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Why do cultured cell lines only have low-medium relevant biological complexity?
Because they are changed so that they can survive, which could skew important pathways
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What is the result of goblet cell metaplasia?
Increase in the number of goblet cells, and therefore an increase in mucus production
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What are mucins?
Proteins that make up mucus
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What type of cells are the progenitors for both goblet and ciliated cells in airways?
Basal cells that sit just underneath the epithelium
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What is polarisation of the epithelium?
The process which defines the specific function of the apical and basolateral membranes
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What happens when epithelial cells are treated with interleukin-13
Basal cells form more goblet cells than ciliated cells, and more mucus is formed
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What is a problem with using primary human bronchial epithelial cells to test drugs?
Low rate of throughput and expensive
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What shape do 3D human cultured epithelial cells form?
Bronchospheres (beachball-like)
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How many proteins are in the human secretome?
4876
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What is the Notch pathway required for?
Regulation of homeostasis in adult tissue, embryonic development and stem cell maintenance
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What are ligands for the Notch receptor?
Delta-like 1/3/4, Jag 1/2
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What happens when a ligand binds to a Notch receptor?
Gamma-secretase cleaves the Notch intracellular domain, triggering a cell signalling cascade
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What is lateral specification in the cochlear?
Having a pattern where there are supporting cells surrounding each hair cell
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What happens if Notch-2 is neutralised in the airway epithelial basal cells?
It inhibits goblet cells from forming and promotes ciliated cell formation
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