Receptor Basics Flashcards
What is constitutive activity?
When a receptor is always activated, even when no ligand is bound
What is affinity?
Ease with which a ligand binds to it’s receptor
Measured in terms of Kd (conc of drug needed to occupy 50% of receptors)
What is efficacy?
Ability of ligand-receptor complex to elicit desired response. Measured in terms of Emax
What is potency?
The amount of drug required to elicit a response of a given intensity. Product of affinity and efficacy. Measured in terms of EC50
What is an allosteric modulator?
Impacts receptor function by binding at allosteric site away from active site
May cause conformational change
Can have efficacy modulators and affinity modulators
What is a neuromodulator?
Biochemical that modulates ability of neurons to respond to neurotransmitters
Can diffuse long distances through neural tissue, to modulates regions of the brain
Chemicals can act as both neurotransmitters and neuromodulators depending on receptor
e.g. D-serine, Glutamate
How do neuromodulators signal?
Through GPCR receptors
Examples of neuromodulators
D-serine Glutamate Dopamine Serotonin Ach
What are the amino acid neurotransmitters (and are they excitatory or inhibitory?)
Glutamate (+)
GABA (-)
Aspartate (+)
Glycine (+ or - depending on receptor)
What are the biogenic amine neurotransmitters?
Ach
Histamine
Monogenic amine: 5-HT
Catecholamines: NA, A, Dopamine
How does NO act as a neurotransmitter?
NO activates cyclicGMP and the MAPK cascade
These pathways lead to increased calcium concentration in the cell
Which increases vesicle exocytosis
What are gliotransmitters?
Molecules released by glial cells - primarily from astrocytes
They are involved in signalling between glial cells and neurons
Modulate excitability by changing intracellular calcium concentrations
Examples of gliotransmitters
Eicosanoids Cytokines Neuropeptides D-Serine Adenosine Glutamate ATP
How many subunits do ionotropic receptors have?
NMDA, AMPA and Kainate have 4
GABAa has 5
What is the most abundant neurotransmitter?
Glutamate
Which glutamate/GABA receptors can be allosterically modulated?
NMDA
GABA-a
GABA-b
Examples of ligands for kinase receptors
Insulin, IGF-1, IGF-2, Prolactin, Lectin, Cytokines
Response times of each receptor type
Ionotropic - milliseconds
GPCR - seconds/minutes
Kinase linked - minutes/hours
Nuclear - hours/days
How are kinase receptors modulated?
By cytokines
How can nuclear receptors affect neurotransmission?
By upregulating expression of genes for small molecule neurotransmitters
What is receptor desensitisation?
Following chronic exposure, when an agonist binds it produces a reduced signalling response
What are the 3 mechanisms that contribute towards receptor desensitisation?
- Receptor internalisation into the membrane
- Reduced expression/synthesis of the receptor
- Homologous desensitisation
What is homologous desensitisation?
Uncoupling of the intracellular response from the ligand-receptor complex
What is tachyphylaxis?
Sudden dramatic decrease in response to a drug, shortly after administration
Usually caused by receptor internalisation
What is tolerance?
Reduced response to a drug following chronic use
Requires an increased dose to produce the same effects
How does receptor desensitisation happen to GPCRs?
Mediated by arrestin proteins
The GPCR is phosphorylated by a GPCR specific kinase (GRK)
Recruitment of the beta-arrestin complex Marks the receptor for internalisation, and re-directs the signalling pathway (homologous desensitisation)
Give an example of a GABA-b agonist
R-Baclofen
Give an example of a GABA-b antagonist
CGP55845
Give and example of an AMPA antagonist
NBQX
