Intermediate Pharmacology (PHAR0009) Notes - Receptors and Signalling

Receptors and Signalling – Summary
Introduction
 Pharmacology – the study of drugs
o Naming of drugs + targets of drug action + selectivity of drugs + measuring ratio of beneficial to
unwanted effects
 Naming drugs
o Classification according to:
 Therapeutic use
 Molecular mechanism of action
 Chemical structure
o Approved name + brand name
 Targets of drug action
o Selective toxicity
 Drugs bind to other sites of action in addition to main site  resulting in unwanted effects
o Magic bullet
 Drug might act selectively at intended site of action
 Has high affinity for cell – only targets main site by aiming with specific chemicals
 Has little effect for organism – minimising damage
 Selectivity of drugs
o Pharmacokinetics – drug motion
 Study of time course of drug absorption + distribution + metabolism + excretion
 Aim to achieve a higher concentration of drug at desired site of action
o Pharmacodynamics – drug power
 Study of biochemical and physiological effects of drugs
 Design drug to have a higher affinity for desired site of action
o Drug targets
 Action at a specific binding site
 Specific macromolecular targets may have high affinity for drug + high specificity –
due to stereochemistry of substrate cofactor binding
o Hormone / neurotransmitter receptors – antagonists or agonists
o Enzymes
o Transporters
o Ion channels
o DNA
 Action not involving a specific binding site
 Drug without identifiable binding site – acts at higher concentrations
o Action of drug is less affected by changes in chemical structure
 Measuring ratio of beneficial to unwanted effects of drugs
o Amount of risk acceptable – influenced by severity of medical condition
o Ehrlick’s therapeutic index
 Ehrlick’s therapeutic index = maximum non-toxic dose / minimum effective dose
 Has difficulties with measurements – due to individual variations to drug
o Therapeutic index – uses better defined doses producing effects in
50% of subjects
 Therapeutic index = TD50 / ED50 = toxic dose / effective dose
 Dose response curve
o Toxicity
 In animal studies – death can be used as a measure of
toxicity
 Therapeutic index = LD50 / ED50 = lethal dose / effective dose

, Receptors and Signalling – Summary
Receptor Structure
 Receptors = protein involved in mediating the effects of intercellular signalling molecules
o Site of action of: neurotransmitters + hormones + growth factors + other intercellular signalling
molecules
o Four structurally distinct families
 Transmembrane receptors
 Ligand-gated ion channels (LGICs)
 G-protein-coupled receptors (GPCRs)
 Kinase-linked and related receptors
 Intracellular receptors
 Nuclear receptors

Ligand-Gated Ion Channels – LGICs
 Ligand-gated ion channels – AKA
o Agonist-activated ion channels
o Neurotransmitter-gated ion channels
o Ionotropic receptors
 Structure
o Multi-subunit (oligomeric) transmembrane proteins – contain a central integral ion channel
 Multiple subunits co-assemble with each other  forming a ring-like structure
 Pentameric – 5 complexes
o nAChRs
o GABAARs
o GlyRs
o 5-HT3Rs
 Tetrameric – 4 complexes
o GluRs
 Trimeric – 3 complexes
o ATP(P2X)Rs
o Extracellular agonist binding site – linked by conformational change to narrow portion of channel
located within lipid bilayer = channel gate
o Neurotransmitter bind to site on extracellular domain  causing conformational change  opening
integral ion channel (excitatory or inhibitory)
 Cation channel = excitatory – causes membrane depolarisation
 Acetylcholine (ACh)
o Nicotinic acetylcholine receptor (nAChR)
 5-hydroxytryptpamine (5-HT)
o 5-HT(serotonin) type 3 receptor (5-HT3R)
 Glutamate (Glu)
o Glutamate receptor (GluR)
 Adenosine triphosphate (ATP)
o ATP (P2X) receptor
 Anion channel = inhibitory – causes membrane hyperpolarisation
 g-aminobutyric acid (GABA)
o GABAA receptor (GABAAR)
 Glycine (Gly)
o Glycine receptor (GluR)
o Subunit structure
 Pentameric LGICs
 Each of the 5 subunits are a single polypeptide