Lecture 2 - Receptors Flashcards
What is a receptor?
Protein in nature Cell constituents that bind agonist - high affinity/specificity Conformational change elicits a cellular response
What will happen if an antagonist binds to a receptor?
Antagonist won’t cause this conformational change
How many supra families of receptors are there?
4
What are the supra families of receptors?
Ligand gated ion channel/ionotropic G-protein coupled receptors Kinase linked receptors Nuclear receptors
Tim scale of ligand gated ion channels/ ionotropic receptors
Milliseconds
Time scale of G-protein couples receptors
Seconds
Time scale of kinase linked receptors
Minutes
Time scale of nuclear receptors
Hours
Examples of ligand-gated ion channels
Nicotinic ACH receptors
Examples of G protein coupled receptors/metabotropic receptors
Muscarinic ACH receptors
Example of kinase linked receptors
Cytokine receptors
Examples or nuclear receptors
Oestrogen receptors
Ligand gated ion channels/ ionotropic
Receptors on which fast neurotransmitters act Opening and closing of ion channel lead to hyperpolaridation or depolarisation
G-protein coupled receptors
Membrane receptors that are coupled to intracellular effector systems via a G protein Contain receptors for many hormones and slow transmitters Endogenous molecule In binding to the receptor
Kinase linked receptors
Large and heterogenous group of membrane receptors responding to protein mediators Comprise extracellular ligand-binding domain linked to intracellular domain by single transmembrane helix Protein phosphorylation and dimerisation of the receptor
Nuclear receptors
Do not always start in the nucleus but will migrate toward here where they will have impact on transcription
Structure of ligand gated ion channels/ionotropic receptors
4 transmembrane domain 3 cytoplasmic loops 16-20 membrane-spanning segment surrounding a central ion channel
Structure of G-protein coupled receptors
7 transmembrane domain Single chain of polypeptide (400-500 residues) Binding domain on outside G protein Coupling domain on the inside
Structure of kinase-linked receptor
One membrane spanning domain Binding domain on outside Catalytic domain on the inside
Structure of type 4 nuclear receptors
No cell membrane DNA binding domain (region where you find zinc fingers)
What is a ligand gated ion prototypical example
nAChR
Ligand gated ion channel structure
Pentameric structure ( 5 subunits) 2 ACH Binding sites at the junction of subunits Number of subtypes exist
What does ligand gated ion channel bind to?
2 molecules of ACH
Major gated Na+ channel, activation results in what?
Change of electrical activity of cell
Where are Na+ channel found?
NMJ Autonomic ganglia CNS
What was the first characterised GPCR?
Beta-adrenoceptor (1986)
What is the typical structure of GPCR?
Typical structure with 7 transmembrane spanning domains
Signal transduction
As there are often a number of metabolic steps involved in signal transduction, they are also referred to as metabotropic
How many distinct families of GPCR?
3
What is family classification of GPCR based on?
Sequence homology
Family A of GPCR
Rhodopsin
Family B of GPCR
Secretin/glucagon receptor family
Family C of GPCR
Metabotrpic Glutamate receptor/ calcium sensor family
Which family is most important in terms of numbers?
Rhodopsin
Rhodopsin receptors
The largest group. Receptors for most amine neurotransmitters, many neuropeptides, purines, prostaglandin our, cannabinoids
Rhodopsin structural features
Short extracellular (N terminal) tail. Ligand binds to transmembrane helices (amine) or to extracellular loops (peptides)
secretin/glucagon receptors
Receptors for peptide hormones, including secretin, glucagon, calcitonin
Structural features of secretin/glucagon receptor family
Intermediate extracellular tail incorporating ligand-Binding domain
Metabotropic Glutamate receptor/ calcium sensor receptors
Small group Metabotropic glutamate receptors, GABA b receptors and Ca2+ sensing receptors
Structural features of metabotropic glutamate receptors
Long extracellular tail incorporating ligand-Binding domain
What is the potential fourth family of GPCR?
Includes many receptors for pheromones but no pharmacological receptors
G proteins are comprised of how many subunits?
3
G protein coupling depends on what?
Whether or not an agonist binds
In the resting state what does G protein consist of ?
Trimer of alpha, beta and gamma subunits
What happens when there is association of trimer with receptors?
Dissociation of GDP from alpha subunit
How is G protein activated?
GTP replaces GDP in cleft and causing alpha subunit to dissociate from the beta gamma dimer
What is the active form of G protein?
Alpha-GTP
What are the G protein targets?
Adenylate cyclase Phospholipase C Ion channels
Adenylate cyclase second messenger
Increases generation of CAMP and subsequent protein kinase activation
Phospholipase C secondary messenger
Increases generation of DAG and IP3 from PIP2
Ion channels secondary messenger
Differentiated from ionotropic receptors by existence of G-protein linkage
What are you GPCR susceptible to?
Desensitisation (or tachyphylaxis or down regulation)
What are the types of tachyphalaxis ?
Homologous and Heterologous
What is homologous tachyphylaxis ?
Effect receptors which the G protein is bound to only
What is heterologous tachyphylaxis?
Effects other receptors not only the ones where G protein is bound
What characterises kinase linked receptor transduction?
This group of receptors are characterised by the presence of an intercellular tyrosine kinase domain
What does kinase linked receptors signal transduction usually involve?
Dimerisation
What does dimerisation allow for in kinase linked receptors?
Autophosphorylatin
Why are kinase linked receptors important ?
Important in many regulatory processes including action of growth factors and cytokines
Nuclear receptor
A receptor family that allows hormone and lipid signals to regulate gene transcription
What do nuclear receptors regulate?
Regulate a host of complex phenomena including development, immune function, organ homeostasis and reproduction
Why is dimerisation of nuclear receptors important?
DNA binding
What does oestrogen do to nuclear receptors?
Oestrogen leads to dimerisation which exposes activation factors
Where do Nuclear receptors reside?
In the cytoplasm or the nucleus
Class I Nuclear receptors
Tend to be hormonal receptor. Present in cytoplasm Operate as homodimers Mainly endocrine ligands High affinity
Class I Nuclear receptors examples
GR, MR, ER, MR
Hybrid class nuclear receptors
Mainly endocrine Operate as RXR heterodimers
Hybrid class nuclear receptors examples
TR and VDR
Class II Nuclear receptors
Retinoid transporters Present in the nucleus Operate as Heterodimers (except RXR) Mainly lipid ligands Low affinity
Class II nuclear receptors examples
PPAR, LXR, FXR, RXR
Examples of non receptor drug targets
Voltage gated channels Transporters Enzymes
