lecture 4 - Basic concepts in neuropharmacology

Question 1

What is a drug?

Answer 1

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.

Question 2

What is a receptor?

Answer 2

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.

Question 3

Two-state model of receptor activation

Answer 3

Question 4

Two-state model of receptor activation

Answer 4

Question 5

Drug

Answer 5

Chemical applied to a physiological system that affects its function in a specific way.

Question 6

Ligand

Answer 6

Any molecule or atom which binds reversibly to a protein

Question 7

Agonist

Answer 7

Drugs which ‘activate’ receptors

Question 8

Antagonist

Answer 8

A drug that binds to the receptor without causing activation, and therefore block the effect of agonists on that receptor

Question 9

The Relation Between Drug Concentration and Effect

Answer 9

Question 10

Different classes of drugs differentially impact the fraction of receptors in the activated (R*) state

Answer 10

Question 11

Antagonists reduce agonist binding

Answer 11

Question 12

Two-state model of receptor activation

Answer 12

prevent agonist
prevent inverse font going back to reverse state

Question 13

Affinity

Answer 13

How well a drug binds its receptor

Question 14

Efficacy

Answer 14

How well a drug once bound to a receptor elicits a response

Question 15

Potency

Answer 15

A measure of the amount of drug required to elicit a response of a given intensity

Question 16

two state model - affinity/ efficacy

Answer 16

Question 17

Potency Vs. Efficacy

Answer 17

Which agonist(s) are the least potent? B

Which drug(s) have the greatest efficacy? A/B

Which drug(s) are partial agonists? C

Question 18

Orthosteric
site

Answer 18

The primary ligand binding site of a receptor

Question 19

Allosteric
site

Answer 19

A site distinct from the endogenous ligand

Question 20

Allosteric modulators impact receptor function by …

Answer 20

binding at a site distinct from the endogenous ligand

Question 21

How does allosteric modulation impact dose response curves?

Answer 21

Question 22

Neurotransmitter =

Answer 22

Biochemical that mediates fast-acting direct communication between two neurons (pre- and post-synaptic)

Question 23

Neuromodulator =

Answer 23

= 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

Question 24

‘Traditional’ Small molecule Neurotransmitters

Answer 24

Question 25

‘traditional’ small molecule transmitters

Answer 25

Examples Glutamate, 5-HT GABA, dopamine Acetylcholine Targets Ligand-gated ion channels, GPCRs Main functional role Fast & Slow synaptic transmission, neuromodulation

Question 26

Neuropeptides

Answer 26

Examples Substance P, Neuropeptide Y, Endorphins Targets GPCRs Main functional role neuromodulation

Question 27

Lipid mediators

Answer 27

Examples Prostoglandins Endocannabinoids Targets GPCRs Main functional role neuromodulation

Question 28

Nitric Oxide

Answer 28

Targets Guanylyl cyclase Main functional role neuromodulation

Question 29

Neurotrophins, cytokines

Answer 29

Examples Brain derived neurotrophic factor, interleukin-1 Targets Kinase-linked receptors Main functional role Neuronal growth, survival, functional plasticity

Question 30

Steroids

Answer 30

Examples Androgens, oestrogens Targets Nuclear and membrane receptors Main functional role Functional plasticity

Question 31

Nitric oxide Signalling modulates neurotransmission

Answer 31

- 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.

Question 32

Glial cells

Answer 32

release transmitters which can modulate neuronal activity

Question 33

Gliotransmitters

Answer 33

Glutamate ATP Adenosine D-serine Eicosanoids (e.g. prostaglandins) Cytokines (e.g. TNFα) Neuropeptides

Question 34

Ionotropic =

Answer 34

Ligand gated ion channels

Question 35

Metabotropic =

Answer 35

Receptors that couple through secondary messenger e.g. GPCRs, tyrosine kinase linked receptors. May indirectly regulate ion channel opening.

Question 36

Ionotropic Receptors (ligand-gated ion channels)

Answer 36

- Activated by binding of neurotransmitters - Channel open Ions flow into the postsynaptic cell: Na+ --> Depolarisation Ca2+ --> Some depolarisation, biochemical cascades, changes in gene expression

Question 37

Ionotropic Receptors (ligand-gated ion channels) types

Answer 37

Question 38

Generic features of ligand-gated ion channels

Answer 38

- 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

Question 39

Metabotropic Receptors

Answer 39

- Not directly coupled to ion channels - Can regulate ion channel opening : --> downstream of neurotransmitter binding --> takes more time

Question 40

G-protein coupled receptors

Answer 40

- 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

Question 41

Stimulation of GPCRs can activate many different downstream effectors

Answer 41

- 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)

Question 42

The main g-protein subtypes

Answer 42

Gαs Gαi/o Gαq Gβg

Question 43

Gαs

Answer 43

Main effectors Stimulates adenylyl cyclase, causing increased cAMP formation Example receptor Catecholamine, Histamine, 5-HT, opioids, cannabinoid

Question 44

Gαi/o

Answer 44

Main effectors Inhibits adenylyl cyclase, causing decreased cAMP formation Example receptor receptors

Question 45

Gαq

Answer 45

Main effectors Activated phospholipase C, increasing production of second messengers e.g. inositol triphosphate and diacylglycerol Example receptor Amine, prostanoid and peptide receptors

Question 46

Gβy

Answer 46

Main effectors As for Gα subunits above plus: Ion channels, GPCR kinases, MAPK Example receptor All GPCRs

Question 47

Example GPCR in the CNS: Metabotropic glutamate receptors

Answer 47

Question 48

Kinase linked receptors

Answer 48

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

Question 49

Cytokine receptors

Answer 49

- 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

Question 50

Nuclear (hormone) receptors

Answer 50

Examples – Glucocorticoid receptor, oestrogen receptor, androgen receptor Typically neuromodulatory e.g. steroid hormones can modulate expression of receptors for ‘traditional’ small molecule neurotransmitters

Question 51

Summary: CNS Receptor types

Answer 51