M&R S6 - Receptors and Membrane Turnover + Presentation Content (S7 included) Flashcards
How are chemical signals classified?
By their function
Hormones:
Signalling between cells via the circulatory system
Neurotransmitters:
Signalling at synapses
Local chemical mediators:
Signalling between adjacent cells in the same tissue
What is a ligand?
Any small molecule that binds specifically to a receptor site
What are the two major types of ligand and what are their functions? (broadest terms)
Agonists:
Activates receptors
Antagonist:
Binds without causing activation of receptor
What is a receptor?
A molecule that recognises specifically a second molecule (ligand) or group of molecules and in response to binding brings about the regulation of a cellular process
How are receptors classified?
According to the agonist that they recognise
Sub classification can be made on the basis of their affinity to a series of antagonists
What is the difference between a receptor and an acceptor?
An receptor is always functionally silent when unbound
A ‘receptor’ that operates in the absence of its ligand is an acceptor
What is meant by ‘signal transduction’?
When a ligand binds to a receptor (the signal) a physiological response is generated
(signal results in action - transduction)
How is signal transduction performed with hydrophobic and hydrophillic molecules?
Hydrophobic:
Ligand diffuses through cell membrane and binds to a cytoplasmic or organellar receptor, eliciting a response
Hydrophilic:
Ligand cannot diffuse through the cell membrane and binds to a cell surface receptor, eliciting a response
What governs the responsiveness of a cell to a signalling molecule?
Presence of absence of a specific receptor
What similarities are there between enzymes and receptors?
Both have specific binding sites
Specificity governed by shape of binding cleft
Specificity of binding confers specificity of action
Binding often reversible in both
Ligand binding (receptor) and allosteric regulator binding (enzyme) both induce conformational change and change in activity
No chemical modification of ligand or allosteric regulators
What are the differences between receptors and enzymes?
Affinity:
- Affinity of ligand binding to receptors is typically higher. The concentration of ligand that fills half of available receptors (KD - Disassociation constant) is generally nanomolar to micromolar (10-9 to 10-6)
- Affinity for substrate binding to enzymes is lower. The concentration of a substrate that fills half of all available active sites on enzymes (KM - Michaelis constant) is generally micromolar to millimolar (10-6 to 10-3)
Chemical modification:
- Enzymes catalyse chemical modification of the substrate when bound to an active site, Receptors do not chemically modify ligands
Give some examples of processes that receptors are involved in
Signalling by hormones and local mediators
Neurotransmission
Cellular delivery (Apoprotein E receptors and LDL)
Control of gene expression (thyroid hormone receptors)
Release of intracellular calcium stores (IP3-R)
Immune responses
What are some common mechanisms by which extracellular hydrophilic signals are transduced into a cellular event
Membrane bound receptors with integral ion channels
Membrane bound receptors with integral enzyme activity
Membrane bound receptors which couple to effectors via transducing proteins
Describe the general action of membrane bound receptors with integral ions channels
Agonist binds to the ligand gated ion channel
This results in a conformational change and the opening of the gated channel
The channel then permits flow of ions down the electrochemical gradient
What are the two types of membrane bound receptor with integral ion channels (ligand gated ions channels)?
Classical
Non-classical
Describe the structure of classical membrane bound receptors with integral ion channels (ligand gated ions channels)
Give an example of a receptor with this structure
Pentameric subunits
4 transmembrane domains
Nicitonic Ach receptors (nAchR)
Give an example of a non-classical membrane bound receptor with integral ion channel
Ryanodine receptors (Ca2+)
Describe the general action of membrane bound receptors with integral enzyme activity
Give some examples of such receptors
Agonist binds to the extracellular domain of these receptors
Causes a conformational change which activates intrinsic enzyme activity
This ‘enzyme’ is contained within the structure of the receptor
For example:
Platelet derived growth factor linked directly to tyrosine kinase
Insulin receptor
Describe how tyrosine kinase linked receptors initiate cellular response to the binding of a ligand
Tyrosine kinase linked receptors autophosphorylate upon ligand binding
Phosphorylated tyrosine residues are then recognised by:
- Transducing proteins
E.g. Insulin receptor substrate-1 (IRS-1)
- Enzymes
E.g. Src homology-2 (SH-2) domains
On association with receptor or transducing protein effector enzymes are activated by:
- Tyrosine phosphorylation (in the case of direct association with the receptor)
- Allosterically (when the transducing protein binds the the receptor)
This transduces the message into an intracellular chemical event
What is another name for membrane bound receptors with transducing proteins?
G-protein coupled receptors
OR
Seven transmembrane domain receptors
Describe the structure of a membrane bound receptor with transducing proteins (GPCR)
Contain 7 transmembrane domains, a ligand may bind here
The N terminal end is extracellular, a ligand may bind here
The C terminal end is cytoplasmic, this is the G-protein coupling domain
How do G-protein coupled receptors operate?
Ligand binds to a receptor on the extracellular N terminal region or between the transmembrane regions
The G-protein will then dissociate and signal an effector, this can be an ion channel or an enzyme
Give some examples of membrane bound receptors with transducing proteins
Muscarinic Ach receptors
Dopamine receptors
5-HT receptors
Light, smell and taste receptors
How does the action of G-proteins on an effector vary and what effect does this have?
Can be stimulatory or inhibitory
Can often have an effector that is stimulated and inhibited simultaneously by different G-proteins
This is ‘Integrated signalling’ where the two signals combine to produce a measured effect