M&R 6.1 Receptors in cell signalling Flashcards
Intercellular signalling molecules can be ________ or ________
Secreted (e.g. hormones, NTs, chemical mediators)
Membrane bound (e.g. in contact inhibiton)
What is a ligand?
Any molecule that binds specifically to a receptor site
Define ‘receptor’
A molecule that specifically recognises a ligand or a family of ligands, and ligand binding causes regulation of a cellular process.
In unbound state - functionally silent
Name the 2 main areas of a cell where receptors are found, and what types of ligands might bind to them
On the cell surface (hydrophilic ligands)
Intracellular - in the nucleus or cytoplasm (small hydrophobic ligands, e.g. steroid hormones, thyroid hormones)
Define ‘acceptors’
Molecules whose activities are modified by the binding of ligands
But their basic function can be carried out without the interaction of a ligand
(e.g. VGNCs - operate in absence of ligands but can be modified by them (e.g. by local anaesthetics))
What is higher, the affinity of a substrate for an enzyme site (Km) or the affinity of a ligand for a receptor site (Kd)?
The affinity of ligands for receptor sites sends to be higher (Kd is lower than Km - conc required to fill half the sites is lower)
How are receptors classified and subclassified?
- By the agonist they recognise (e.g. ACh receptor)
- Then by antagonists they recognise (e.g. nicotinic vs muscarinic AChRs
- Then by affinity of antagonists (e.g. M1, M2, M3 mAChRs each have a more selective affinity for a certain antagonist)
What are some similarities between receptor binding sites & enzyme binding sites (both active & regulatory)?
- Binding is site specific
- Specificity governed by shape of binding cleft
- Specificity of binding confers specificity of outcome
- Binding is often reversible
- Binding can induce a conformational change (e.g. induced fit) and a change in activity
- In both receptors and enzyme regulatory sites, the ligand is not chemically changed
What are some differences between receptor binding sites and enzyme binding sites?
- Ligand->receptor has higher affinity than substrate->enzyme
- Substrates binding to enzyme active sites get chemically changed, ligand binding to receptors do not
Name 4 common mechanisms by which extracellular signals are transduced into intracellular events
- Via membrane-bound receptors with integral ion channels
- Via membrane bound receptors with integral enzyme activity (e.g. tyrosine kinase)
- Via membrane bound receptors which couple to effectors via tranducing proteins (e.g. GPCRs)
- Via intracellular receptors (for hydrophobic ligands)
‘Classical’ ligand-gated ion channels have how many subunits and TM domains? Where is the binding domain?
5 subunits (pentameric structures) Each subunit has 4 TM domains (Domain #2 forms the pore lining)
The N terminal forms the binding domain.
How are ligand-gated ion channels selective for certain ions?
They have a ring of charged amino acid residues in the gating area.
E.g. a nAChR is selective for cations, so has a ring of negatively charged residues
Name some classical ligand-gated ion channels, and the ions they allow through
nAChR (gated cation channel - Na+, K+, Ca2+) GABA receptor (gated Cl- channel) Glycine receptor (gated Cl- channel) Glutamate receptors (e.g. NMDA, AMPA - gated Ca2+ channels)
Name some non-classical ligand-gated ion channels
ATP-sensitive K+ channel IP3 receptor Ryanodine receptor (gated Ca2+ channel)
In general terms, how do membrane-bound receptors with integral enzyme activity work?
Agonist binds to the extracellular domain and causes a conformational change, which activates an intrinsic enzyme activity contained within the structure of the receptor.
Name 2 enzymes that can be linked with receptors
Tyrosine Kinase Guanylyl cyclase (GTP-->cGMP)
All growth factors act via ________ _________ - linked receptors
Tyrosine kinase
they all effectively want to send the same message so they all act in the same way in order to have the same effect
Receptors with integral enzyme activity tend to have ___ parts. Why?
2 parts (they are dimers) So they can move relative to each other and reveal an active site that wasn't available before
Describe how tyrosine-kinase linked receptors work
Agonist (e.g. hormone) binds to extracellular binding sites
This activates protein kinase activity in the cytoplasmic domain, which autophosphorylates tyrosine residues (Y) on the cytoplasmic domain
Phosphorylated tyrosine residues (P-Y) can be recognised:
- -> directly by enzymes containing phosphotyrosine recognition sites [SH2 domain]
- -> by transducing proteins (e.g. IRS1) which then activate an enzye
The enzyme transduces the message into an intracellular chemical event
In general terms, how do GPCRs transduce an extracellular signal into an intracellular event?
Binding of ligand causes a conformational change which activates GDP/GTP exchange in G proteins.
G proteins transduce the message onto an enzyme or channel in the membrane
Briefly describe the structure of a GPCR
7 TM domains
Ligand binding site on N terminal
G-protein coupling domain on C-terminal
G protein has 3 subunits (alpha, beta and gamma) - splits into alphas and beta-gamma subunits. Alpha subunit can vary (e.g. s, i, q)
What kinds of ligands bind to intracellular receptors? Name some examples.
Hydrophobic ligands e.g. steroid hormones (cortisol, oestrogen, testosterone) or thyroid hormones (T3 & T4)
What are intracellular receptors like at rest and what happens when they are activated?
In the resting state they are stabilised by association with heat-shock or chaperone proteins
When activated, the receptor dissociates from the chaperone proteins and translocates to the nucleus. In the nucleus it binds to control regions in DNA to regulate gene expression
Are the effects of intracellular receptors fast or slow?
Relatively slow, because transcription and translation are required
Name some cells whose processes can be either activated or inhibited depending on which receptor is stimulated
Hepatocytes (insulin stimulates glycogen synthesis, glucagon stimulates glycogen breakdown)
Cardiac pacemaker cells (NA acting at beta1 adrenoceptors increases heart rate, whereas ACh acting at M2 mAChRs decreases heart rate)
