L2 - Receptor Superfamilies

what are the four main classifications of drug targets

receptors, ion channels, enzymes, transporters

what are the two main pathways an agonist can cause an effect upon binding to a receptor

directly, through transduction mechanisms

what is an example of a direct effect an agonist may have upon binding

ion channel opening or closing

what are three basic examples of transduction mechanisms

enzyme activation/inhibition, ion channel modulation, DNA transcription

what is different about antagonists compared to agonists

antagonists do not cause a direct biological effect

what are the two main ways ion channels can respond to stimuli/drugs

as a receptor by binding to a ligand, by responding to physical stimuli like pressure or changes in membrane potential

what are the two main ways drugs act on ion channels

as blockers, as modulators that increase or decrease the opening probability

which drug target is an especially important one

enzymes

what are the three main ways drugs can interact with enzymes

inhibitors, false substrates which produce an abnormal metabolite, prodrugs which are changed into an active drug

what is a prodrug

a drug that has no biological effect until it has been metabolised in some way

where do transporters sit

in cell membranes

what are the two main ways drugs can act on transporters

inhibitors, false substrates which accumulate an abnormal compound

what properties do ligands that bind to cell surface receptors have

water soluble, short half lives

what properties do ligands that bind to intracellular receptors have

lipophilic

what are ionotropic receptors

ligand gated ion channels

what are the key features of ionotropic receptors

membrane spanning, millisecond activation, hyperpolarization/depolarization

give a brief overview of what happens when a ligand binds an ionotropic receptor and of their structure

causes a conformational shift in the ion channel which is essentially either closed or open, binding domain is outside, has a series of transmembrane domains which line the pore

what are metabotropic receptors

G protein coupled receptors

give a brief overview of metabotropic receptors

membrane spanning, activation in seconds, second messengers/protein phosphorylation (needs other proteins to produce their effect)

give a brief overview of ligand binding to metabotropic receptors and their structure

ligand binds on outside of cell, causes a conformational change, can change ion permeability or initiate second messenger systems, can involve calcium release, phosphorylation, etc, has seven transmembrane domains, intracellular G protein coupling domain

give a brief overview of kinase linked receptors

membrane spanning, activation in hours, protein phosphorylation causing changes in gene transcription and protein synthesis

why is the biological effect of kinase linked receptors slow

protein phosphorylation doesn’t lead to cascades, the effects are limited by the speed of gene transcription

brief overview of kinase linked receptor structure

extracellular binding domain, single transmembrane domain, intracellular catalytic domain

brief overview of kinase linked receptor action

ligand binds to extracellular domain, activates intracellular kinase domain, kinase transfers phosphate from ATP onto specific amino acids on the receptor or other proteins, triggers downstream signalling pathways

brief overview of intracellular receptors

ligand must pass through cell membrane, transduction of effect takes hours, leads to changes in gene transcription and protein synthesis

brief intracellular receptor structure

binding domain, DNA binding domain (zinc fingers), no membrane spanning domain

where can intracellular receptors be found

nucleus, cytosol

do the effects of intracellular receptors always lead to an increase in gene transcription

no, can also decrease or turn off transcription

what percentage of prescription drugs target intracellular receptors

15%

how many intracellular receptors are there

48

what are some examples of steroid hormones

oestrogen, testosterone, cortisol, aldosterone, progesterone

what diseases are orphan receptors involved in

diabetes, high cholesterol

what is another way to think of intracellular receptors

as ligand activated transcription factors

do intracellular receptors exist in isolation

no, they exist as a complex of different proteins, some hold the receptor in a specific location

what happens to accessory proteins of intracellular receptors upon binding

some proteins are removed, some are recruited