l16 pharm

what are the 4 main receptor families?

1. ligand-gated ion channels 2. GPCRs 3. kinase-linked receptors 4. nuclear receptors

what is a ligand-gated ion channel?

a receptor in the cell membrane that opens an ion channel when a ligand binds, allowing ions to move across the membrane

why are ligand-gated ion channels fast?

because once the ligand binds, the channel opens directly and ions move immediately across the membrane

what is the time frame of ligand-gated ion channels?

milliseconds / fractions of a millisecond

what is another name for ligand-gated ion channels?

ionotropic receptors

what is the main response caused by ligand-gated ion channels?

they change ion movement across the membrane, causing depolarisation or hyperpolarisation

what is a GPCR?

a membrane receptor that activates G-proteins and second messenger pathways after ligand binding

what is the time frame of GPCR signalling?

seconds

what is a kinase-linked receptor?

a membrane receptor that activates phosphorylation pathways, often changing gene transcription

what is the time frame of kinase-linked receptors?

usually hours

what is a nuclear receptor?

an intracellular receptor that directly regulates gene transcription after binding a lipid-soluble ligand

what is the time frame of nuclear receptors?

hours, because they change gene transcription and protein synthesis

what key things should you know for each receptor family?

location, structure, how it produces a response, time frame, and an example drug/receptor

what are receptor subtypes?

different versions of receptors within the same receptor family that can bind the same endogenous ligand but cause different effects

why can one neurotransmitter have multiple effects?

because it can bind to different receptor subtypes, and each subtype may signal differently or be located in different places

what are serotonin receptors also called?

5-HT receptors

why are serotonin receptors a good example of receptor subtypes?

because serotonin/5-HT can bind many receptor subtypes, such as 5-HT1, 5-HT2, 5-HT3, 5-HT4, 5-HT5, 5-HT6 and 5-HT7

which serotonin receptor subtype is a ligand-gated ion channel?

5-HT3

what type of receptors are most serotonin receptors?

GPCRs

why are receptor subtypes important for drug development?

because subtype-selective drugs can target specific effects/cells and hopefully reduce side effects

what does it mean if receptor subtypes have different coupling?

different subtypes can activate different intracellular pathways, e.g. Gs, Gi, or Gq pathways

can the same ligand act on both GPCRs and ligand-gated ion channels?

yes, some ligands can act on both, e.g. serotonin acts on GPCR subtypes and the 5-HT3 ligand-gated ion channel

what are the 3 key properties of ligand-gated ion channels?

they are activated by specific ligands, conduct ions across membranes, and select between different ions

why can’t ions just freely cross the membrane?

ions are charged, so they need channels to cross the lipid membrane

what determines which ions pass through a ligand-gated ion channel?

the structure of the pore, especially the amino acids lining it

what is GABA?

a major inhibitory neurotransmitter in the nervous system

what does inhibitory mean in the nervous system?

it makes a neuron less likely to fire an action potential

what type of receptor is GABA-A?

a ligand-gated ion channel

what happens when GABA binds to GABA-A receptors?

the channel opens and chloride ions can move into the cell

what ion moves through GABA-A receptors?

chloride ions, Cl-

what happens when chloride enters a neuron?

the inside becomes more negative, causing hyperpolarisation

what does hyperpolarisation do to a neuron?

makes the neuron less likely to fire an action potential

why is GABA-A inhibitory?

because it allows Cl- movement that hyperpolarises the cell and reduces neuronal excitability

what does pentameric mean?

made of 5 subunits

why is the GABA-A receptor called pentameric?

because the functional receptor is made from 5 subunits

why can there be different versions of GABA-A receptors?

because different alpha, beta, gamma and other subunits can combine in different ways

what is an orthosteric site?

the normal binding site for the endogenous ligand

what is the orthosteric site on GABA-A receptors?

the GABA binding site

what is an orthosteric agonist?

a drug that binds the normal ligand site and activates the receptor

what is an orthosteric antagonist?

a drug that binds the normal ligand site and blocks activation by the endogenous ligand

what is an allosteric site?

a binding site that is separate from the normal endogenous ligand binding site

what is allosteric modulation?

when a drug binds to a different site from the orthosteric site and changes how the receptor responds

do benzodiazepines bind to the GABA binding site?

no, they bind allosterically to a different site on GABA-A receptors

how do benzodiazepines affect GABA-A receptors?

they make GABA’s effect stronger by increasing chloride conduction when GABA is bound

why do benzodiazepines cause sedation/anxiolysis?

they enhance GABA-A inhibition, making neurons less excitable

do benzodiazepines activate GABA-A receptors without GABA?

generally no, they enhance the effect of GABA when GABA is bound

what is affinity?

how strongly a ligand binds to a receptor

what is efficacy?

how well a ligand-receptor interaction produces a response

what can an allosteric modulator change?

it can increase or decrease the affinity and/or efficacy of the orthosteric ligand

what is a PAM?

a positive allosteric modulator, which increases affinity and/or efficacy of the orthosteric ligand

what is a NAM?

a negative allosteric modulator, which decreases affinity and/or efficacy of the orthosteric ligand

what happens to a concentration-response curve with an efficacy-increasing PAM?

the maximum response increases because the ligand can produce a bigger effect

what does increased Emax mean?

the maximum possible response is higher

what does a left shift in a concentration-response curve usually suggest?

increased potency/affinity, meaning less ligand is needed for the same response

what part of ligand-gated ion channels forms the pore in GABA-A?

TM2 helices from each subunit line the pore and help form the gate

what happens to the GABA-A pore when GABA binds?

the receptor changes shape and the pore opens

what is the receptor pore?

the opening through the receptor that ions pass through

what determines ion selectivity in the receptor pore?

amino acids lining the pore, especially in the TM2 region

what happens when excitatory ligand-gated ion channels open?

Na+ and/or other positive ions enter, making the inside of the cell more positive

what is depolarisation?

when the inside of the cell becomes less negative/more positive

what does depolarisation do to action potential probability?

increases the chance of an action potential

what happens when inhibitory ligand-gated ion channels open?

Cl- enters or negative charge increases inside, making the cell more negative

what is hyperpolarisation?

when the inside of the cell becomes more negative

what does hyperpolarisation do to action potential probability?

decreases the chance of an action potential

what are examples of excitatory neurotransmitters at ligand-gated ion channels?

acetylcholine and glutamate

what are examples of inhibitory ligand-gated ion channels?

GABA-A receptors and 5-HT3-related inhibitory/excitability-modifying channels depending on context

what are benzodiazepines?

allosteric modulators of GABA-A receptors that enhance GABA signalling

what are barbiturates?

allosteric modulators of GABA-A receptors that enhance inhibitory signalling

what is muscimol?

an orthosteric agonist at GABA-A receptors

what is flumazenil used for?

reversal of benzodiazepine effects/overdose

what is nicotine?

an orthosteric agonist at nicotinic acetylcholine receptors

what is varenicline?

a nicotinic receptor partial agonist used for smoking cessation

what is pancuronium?

a nicotinic acetylcholine receptor antagonist used as a muscle relaxant

what is the NMDA receptor?

a glutamate ligand-gated ion channel involved in excitatory signalling

what does ketamine do at NMDA receptors?

it blocks the channel and can act as an anaesthetic/antidepressant drug

what does memantine do at NMDA receptors?

it reduces excessive/prolonged calcium entry

what do kinase-linked receptors commonly respond to?

growth factors, cytokines, and some hormones such as insulin

what processes are kinase-linked receptors involved in?

cell division, metabolism, growth, differentiation, inflammation, apoptosis and immune responses

what is the basic structure of kinase-linked receptors?

extracellular ligand-binding domain, single transmembrane domain, and intracellular signalling domain

how many times do kinase-linked receptors usually cross the membrane?

once

what is phosphorylation?

adding a phosphate group to a protein

what is a kinase?

an enzyme that adds phosphate groups to proteins

what is a phosphatase?

an enzyme that removes phosphate groups from proteins

why is phosphorylation important?

it can activate or inactivate proteins and trigger signalling pathways

what is a receptor tyrosine kinase?

a kinase-linked receptor with an intracellular tyrosine kinase domain

why are receptor tyrosine kinases important in cancer?

mutations can make them overactive, causing excessive growth and division signalling

what happens when a growth factor binds a receptor tyrosine kinase?

receptors dimerise, phosphorylate tyrosines, recruit signalling proteins and activate kinase cascades

what is dimerisation?

when two receptor molecules come together

what is autophosphorylation?

when a receptor phosphorylates itself or its paired receptor after activation

what happens after RTK autophosphorylation?

phosphorylated tyrosines become docking sites for intracellular signalling proteins

what are SH2 domain proteins?

proteins that bind phosphorylated tyrosine residues on activated receptors

what is a kinase cascade?

a chain reaction where one kinase activates another kinase, amplifying the signal

what is the Ras/Raf/MEK/MAPK pathway?

a kinase signalling cascade that can lead to changes in gene transcription

what are cytokine receptors?

kinase-linked receptors that lack intrinsic enzyme activity but signal through associated kinases

what does it mean that cytokine receptors lack intrinsic enzyme activity?

the receptor itself is not the kinase; it recruits/uses separate kinase enzymes

what pathway do many cytokine receptors use?

the JAK-STAT pathway

what happens in the JAK-STAT pathway?

cytokine binds, JAKs activate, STATs are phosphorylated, STATs dimerise and enter the nucleus to change transcription

what is a STAT protein?

a transcription factor activated by phosphorylation in cytokine receptor signalling

what is a JAK?

a kinase associated with cytokine receptors

why are kinase-linked receptors slower than ion channels?

because they activate phosphorylation cascades and often change gene transcription