Revision 6: Receptors and Membrane Turnover Flashcards
Definitions of receptor, acceptor, ligand
Receptor: recognises specifically a 2nd molecule (ligand)/family of molecules and, in response to binding, brings about regulation of a cellular process
- classified according to the specific physiological signalling molecule that they recognise
- silent at rest
Acceptor: same as receptor definition, however it operates in the absence of a ligand
Ligand: molecule that binds specifically to a receptor site
- Agonist: activation of receptor
- Antagonist: does not activate, blocks receptor
Explain why signal transduction is needed
small Hpho. molecules are capable of passing straight through the PM and binding to IC receptors, these don’t need signal transduction
- penetrate PM -> bind to monomeric receptors in cytoplasm/nucleus -> receptor dissociates from heat shock/chaperone prot.s -> translocates to nucleus -> binds to control regions in DNA (defined by specific sequences) -> regulate gene expression
- >relatively slow in comparison to signal transduction as transcription and translation are required
however, Hphi molecules do need ST, and work through intergal ion channels, integral enz. activity or coupling to effectors through transducing prot.s
types of signal transduction
1 Integral Ion channel: agonist binds -> conformational change -> opening of gated ion channel
-Two types of ion channel: non classical (eg Ryanodine calcium receptor) and classical (share similar pentameric subunit structures w/ 4 transmembrane domains eg nAChr)
2 Integral enz. activity: agonist binds -> conf. change -> activates intrinsic enz. activity eg PDGF linked to Tyr. Kin.
- Tyr. Kin. linked receptors autophosphorylate when the ligand binds, recognised by either enz.s w/ phosphotyrosine recog. sites called SRC-homology-2 (SH2) domains or transducing prot.s eg IRS-1 (insulin receptor substrate-1) that then activate enz.s
- > the enz.s are activated allosterically/by Tyr. phosphorylation by receptor kinase -> transuction of message into an IC chem. event
3 Coupling to effectors through transducing prots: 7 TMDRs (a family known as GPCRs) couple -> effector molecules via a transducing prot., a GTP-binding regulatory protein (G-protein), the effector molecules can be enz.s (eg adenyl cyclase) or ion channels (Calcium/potassium)
-often, separate GPCRs act simultaneously -> stim. and inh. the effector (known as integrated signalling) -> inputs combine to produce a measured effect
Types of signal transduction: Integral ion channels
agonist binds -> conf. change -> opening of gated channel
can be classical (pentameric subunit structure, 4 transmembrane domains eg nAChr) or non classical (rare eg ryanodine)
types of signal transduction: intergal enz. activity
agonist binds -> conf. change -> activates intrinsic enz. activity eg PDGF is linked to Tyr. Kin.
Tyr. Kin. linked receptors autophosphorylate when the liagnd binds, recognised by enz.s directly if they have phosphotyrosine recog. sites (SRC-homology-2 - SR2 - domains) or by transducing prot.s eg IRS-1 (insulin receptor substrate-1) that then activate enz.s
-enz.s are activated allosterically/by Tyr. phosphorylation by receptor kinase -> transduces message into IC chem. event eg insulin receptor
Types of signal tranduction: coupling to effectors through transducing prot.s
7 TMDRs (family aka GPCRs) couple to effector molecules via a transducing molecule, a GTP-binding regulatory protein (G-protein) - the effectors are enz.s eg adenyl cyclase or ion channels ie calcium, potassium
often, separate GPCRs act simultaneously, stim. and inh. the effector -> Integrated Signalling -> inputs combine to produce a measured effect
explain amplification
eg enz. stim.
-binding of signalling molecule to 1 receptor -> modification of 100s or 1000s of substrate molecules -> enz. cascade
Describe phagocytosis and pinocytosis
Phagocytosis: specialised cells
- after binding of one particle to receptor the cell sends out extensions of pseudopods that paermit more receptor interactions via membrane zippering technique leading to membrane invagination/particle internalisation
- phagosome + lysosome -> phagolysosome -> degradation of its contents
- allows clearance of debris and pathogens
Pinocytosis: invag. of PM to form a lipid vesicle
- uptake of impermeable EC solutes and retrieval of the PM
- Fluid phase and Receptor mediated endocytosis (RME) are types
- > former is non specific uptake of many small molecules
- > latter is specific binding of molecules to cell surface receptors that permits the selective uptake of substances into cell
Cholesterol uptake
uses RME, type 1
LDLs originate in liver, contain a core of cholesterol that has been esterified to FAs and is surrounded by a lipid monolayer containing phospholipids, cholesterol and apoprotein B
Cells that want to absorb the LDLs synthesise LDL receptors that recog. Apoprot. B and are localised in clusters over clathrin coated pits that form spontaneously
When the LDL binds, the pit invaginates -> coated vesicles -> uncoated vesicles (via ATP hydrolysis) -> fuse w/ larger smooth vesicles called endosomes -> the low pH (5.5-6) causes the LDL and receptor to dissociate
- the receptor is sequestered to a domain w/in the endosome and buds off -> perhaps via golgi -> recycled to PM
- the endosome w/ LDL fuses w/lysosomes -> cholesterol hydrolysed from ester and is released into the cell
Explain Fe3+ uptake
Type 2 RME
2 Fe3+ bind to apotransferin -> transferin -> binds to transferin receptor (at neutral pH) -> invag. of PM -> coated -> uncoated etc -> fuse w/ endosomes -> Fe3+ dissociates and enters cell -> but apotransferin remains bound to tranferin receptor -> sorted in CURL -> recycled back to PM
Explain insulin uptake
Type 3 RME
in endosome the insulin remains bound to the receptor, the complex is targetted to lysosome for degradation -> reduction of insulin receptors -> desensitisation of cell to insulin
the receptors ONLY congregate over clathrin pits when the agonist is bound
Transcytosis
Type 4 RME
ligands bound to receptors are sometimes transported across the cell
eg transferal of maternal ABs to foetus
-Immunoglobulin A from circulation to bile in the liver, the receptor is cleaved and IgA is released w/ secretory component derived from the receptor
compare and contrast RME modes
fate of receptor: 1 recycled 2 recycled 3 degraded 4 transported
fate of ligand: 1 degraded 2 recycled 3 degraded 4 transported
Examples: 1 LDL 2 transferin 3 insulin, Epidermal GF, immune complexes 4 maternal IgG, IgA
Function: 1 metabolite uptake 2 metabolite uptake 3 receptor down regulation, removal from circulation of foreign antigen 4 transfer of large molecules across PM eg maternal immunity to foetus across placenta, circulation to bile
how can RME type 3 be a model for the development of type 2 diabetes
How do pathogens take advantage of RME?
Membrane enveloped viruses and toxins
exploit endocytic pathways to enter cells after a CHANCE binding to receptors in the PM
endosome’s low pH allow viral membrane to fuse with the endosomal membrane -> releases viral RNA into cell -> translated and replicated by host
eg cholera and diphtheria toxin
