lecture 4 - Basic concepts in neuropharmacology Flashcards
What is a drug?
A chemical substance of known structure, other than a nutrient or an essential dietary ingredient, which, when administered to a living organism, produces a biological effect.”
With some exceptions, drugs act on target proteins, namely:
– receptors
– enzymes
– carriers
– ion channels.
What is a receptor?
Protein molecules whose function is to recognise and respond to endogenous chemical signals.”
NB: ‘Receptor’ is sometimes used to denote any target molecule with which a drug molecule has to combine in order to elicit its specific effect.
For example, the voltage-sensitive sodium channel is sometimes referred to as the ‘receptor’ for local anaesthetics or the enzyme dihydrofolate reductase as the ‘receptor’ for methotrexate.
Two-state model of receptor activation
Two-state model of receptor activation
Drug
Chemical applied to a physiological system that affects its function in a specific way.
Ligand
Any molecule or atom which binds reversibly to a protein
Agonist
Drugs which ‘activate’ receptors
Antagonist
A drug that binds to the receptor without causing activation, and therefore block the effect of agonists on that receptor
The Relation Between Drug Concentration and Effect
Different classes of drugs differentially impact the fraction of receptors in the activated (R*) state
Antagonists reduce agonist binding
Two-state model of receptor activation
prevent agonist
prevent inverse font going back to reverse state
Affinity
How well a drug binds its receptor
Efficacy
How well a drug once bound to a receptor elicits a response
Potency
A measure of the amount of drug required to elicit a response of a given intensity
two state model - affinity/ efficacy
Potency Vs. Efficacy
Which agonist(s) are the least potent? B
Which drug(s) have the greatest efficacy? A/B
Which drug(s) are partial agonists? C
Orthosteric
site
The primary ligand binding site of a receptor
Allosteric
site
A site distinct from the endogenous ligand
Allosteric modulators impact receptor function by …
binding at a site distinct from the endogenous ligand
How does allosteric modulation impact dose response curves?
Neurotransmitter =
Biochemical that mediates fast-acting direct communication between two neurons (pre- and post-synaptic)
Neuromodulator =
= Biochemical that modulates activity of neurons and neural networks by changing the ability of neurons to response to neurotransmitters. Can act locally or at sites remote from where they are synthesized.
Some neurotransmitters can also act as neuromodulators
‘Traditional’ Small molecule Neurotransmitters
‘traditional’ small molecule transmitters
Examples
Glutamate, 5-HT
GABA, dopamine
Acetylcholine
Targets
Ligand-gated ion channels, GPCRs
Main functional role
Fast & Slow synaptic transmission,
neuromodulation
Neuropeptides
Examples
Substance P, Neuropeptide Y, Endorphins
Targets
GPCRs
Main functional role
neuromodulation
Lipid mediators
Examples
Prostoglandins
Endocannabinoids
Targets
GPCRs
Main functional role
neuromodulation
Nitric Oxide
Targets
Guanylyl cyclase
Main functional role
neuromodulation
Neurotrophins, cytokines
Examples
Brain derived neurotrophic factor, interleukin-1
Targets
Kinase-linked receptors
Main functional role
Neuronal growth, survival, functional plasticity
Steroids
Examples
Androgens, oestrogens
Targets
Nuclear and membrane receptors
Main functional role
Functional plasticity
Nitric oxide Signalling modulates neurotransmission
- Ca2+ influx into cells downstream of ion-channel opening leads to activation of neuronal nitric oxide synthase (nNOS) which increases intracellular nitric oxide (NO) levels.
- NO activates cGMP and MAPK signalling which modulates function of the postsynaptic neuron.
- NO can also diffuse retrogradely and impact neurotransmitter release from the presynaptic neurons.
Glial cells
release transmitters which can modulate neuronal activity
Gliotransmitters
Glutamate
ATP
Adenosine
D-serine
Eicosanoids (e.g. prostaglandins)
Cytokines (e.g. TNFα)
Neuropeptides
Ionotropic =
Ligand gated ion channels
Metabotropic =
Receptors that couple through secondary messenger e.g. GPCRs, tyrosine kinase linked receptors. May indirectly regulate ion channel opening.
Ionotropic Receptors (ligand-gated ion channels)
- Activated by binding of neurotransmitters
- Channel open
Ions flow into the postsynaptic cell:
Na+ –> Depolarisation
Ca2+ –> Some depolarisation, biochemical cascades, changes in gene expression
Ionotropic Receptors (ligand-gated ion channels) types
Generic features of ligand-gated ion channels
- Typically heteromeric assemblies of 4 or 5 subunits
- Each subunit has transmembrane spanning helices which when assembled form a central aqueous channel
- Ligand binding –> channel opening = milliseconds
Metabotropic Receptors
- Not directly coupled to ion channels
- Can regulate ion channel opening :
–> downstream of neurotransmitter binding
–> takes more time
G-protein coupled receptors
- Ligand binding induces GDP to GTP exchange on the Gα subunit
- Gα subunit dissociates from βy complex
- Gα subunit and βy complex activate downstream targets
- When bound to target GTPase activity of Gα subunit is increased leading to hydrolysis of GTP to GDP
Stimulation of GPCRs can activate many different downstream effectors
- Adenylyl cyclase (AC) – cAMP formation
- Phospholipases
- PLC = inositol phosphate and diacylglycerol formation
- PLA2 = arachidonic acid (AA) and ecosanoid formation
- Kinases e.g. MAPK, PI3K
- Ion channels
- Gene transcription (via MAPK, PKA/CREB)
The main g-protein subtypes
Gαs
Gαi/o
Gαq
Gβg
Gαs
Main effectors
Stimulates adenylyl cyclase, causing increased cAMP formation
Example receptor
Catecholamine, Histamine, 5-HT, opioids, cannabinoid
Gαi/o
Main effectors
Inhibits adenylyl cyclase, causing decreased cAMP formation
Example receptor
receptors
Gαq
Main effectors
Activated phospholipase C, increasing production of second messengers e.g. inositol triphosphate and diacylglycerol
Example receptor
Amine, prostanoid and peptide receptors
Gβy
Main effectors
As for Gα subunits above plus:
Ion channels, GPCR kinases, MAPK
Example receptor
All GPCRs
Example GPCR in the CNS: Metabotropic glutamate receptors
Kinase linked receptors
1 and 2. Ligand-binding leads to dimerization of receptors
3. Receptor dimers undergo auto-phosphorylation at tyrosine (Tyr) residues
4. pTyr sites recruit proteins with SH2 domains leading to activation of downstream signalling e.g. STAT transcription factors, members of the RAS/Raf/MAPK pathway
Cytokine receptors
- are tyrosine kinase linked receptors
- Cytokines are neuromodulators in the CNS
- Can activate multiple down stream signalling cascades including transcription factors that modulate gene expression
- Cytokine receptors are regulated by endogenous negative feedback mechanisms
Nuclear (hormone) receptors
Examples – Glucocorticoid receptor, oestrogen receptor, androgen receptor
Typically neuromodulatory e.g. steroid hormones can modulate expression of receptors for ‘traditional’ small molecule neurotransmitters
Summary: CNS Receptor types
