Lecture 11- Biological signalling and receptors Flashcards
define receptor
a molecule that recognises specifically a molecule (ligand) or family of molecules which in response to ligand binding brings about regulation of a cellular process
receptors in an unbound state
functionally silent
role of receptors
- Neurotransmission - cellular deliver - control of gene expression - signalling by hormones - cell adhesion - modulation of the immune response - sorting of intracellular proteins - release off intracellular calcium stores
two main type of receptors
cell surface intracellular
cell surface receptors
tyrosine kinase GPCR Ligand gated Voltage gated
intracellular
nuclear e.g. steroids
ligand
any molecule which binds specifically to a receptor site
agonist
• May produce activation of a receptor
antagonist
• Oppose the action of agonist activation
signalling between cells via 92)
-secreted molecules - plasma membrane bound molecules (APCs)
types of signalling via secrete molecules
paracrine endocrine synaptic
paracrine
• Signalling molecule secreted into tissue and acts on adjacent cells • Local signal
endocrine
• If signalling molecule travels around the circulation to find target cell in different tissue • E.g. hormones
synaptic
• NT released in the junction b/w 2 nerve cells • E.g. NMJ
three main types of chemical signalling
• Local chemical mediators • Hormones • NT
difference between receptors and acceptors
Receptors are silent at rest, whilst acceptors operate in the absence of ligand/ Agonist binding to the receptor will stimulate biological response, whilst in acceptors, binding alone produces no response
affinity in enzymes
km
affinity in receptors
Kd
affinity of ligand binding at receptor site is generally much …… than binding of substrate and allosteric regulators to enzyme site
higher
receptors are classified according to
1) the agonist it recognises 2) affinity of a series of agonists 3) affinity of antagonists
affinity of a series of agonists e.g…
i. Nicotinic- higher affinity to nicotine ii. Muscarinic- higher affinity to muscarine
affinity of antagonists e.g..
• M1- antagonist= pirenzipine • M2- antagonist= gallamine • M3- antagonist= hexahydrosilodiphenol
the agonist it recognises e.g.
adrenoreceptors
types of receptors (4)
- Membrane-bound receptors with integral ion channel o Ligand-gated nAChR 2. Membrane-bound receptors with integral enzyme activity o GPCR- adrenaline 3. Membrane bound receptors which couple to effectors through transducing proteins o Tyrosine kinase- insulin 4. Intracellular receptors o Steroid receptors- oestrogen
Membrane-bound receptors with integral ion channel e.g.
o Ligand-gated nAChR
Membrane-bound receptors with integral enzyme activity
o GPCR- adrenaline
Membrane bound receptors which couple to effectors through transducing proteins
o Tyrosine kinase- insulin
Intracellular receptors
o Steroid receptors- oestrogen
receptors on the cell surface for
hydrophilic signalling molecules
receptors within the cell for
hydrophobic signalling molecules
steroids can pass the lipid bilayer due to being
hydrophobic and small
hydrophobic is used interchangeable with
lipophilic- will pass the membrane
polar molecules
will not pass the membrane
how are steroid transported
through the bloods on proteins such as albumin
where are steroidal receptors
int he cytoplasm or nucleus
steroids work to
activate or inhibit the expression of genes
classical ligand gated ion channel
- nAChR- gated Na+, K+, Ca2+ channel - Gaba receptor- gated chloride channel - Glycine receptor- gated chloride channel - Glutamate receptor- gated entry of Ca2+
nicotinic acetylcholine receptor
- Fastest mode of transport into the cell - Ligand-gated receptor (all have a pentameric structure)
structure of nicotinic acetylcholine receptor
Pentameric- 2 subunits related to ACH binding- all subunits involved in resting pore
outline how nicotinic acetylcholine receptor causes influx of sodium and depolarisation
1) ACh binds to the receptor 2) Causes the gate to open 3) Na+ can flood into cell and cause depolarisation of end plate
non classical ligand gated ion channels
- ATP-sensitive K+ channel - Ryanodine receptor (calcium)
example of a membrane bound receptor with integral enzyme activity
signalling via Tyrosine Kinases
tyrosine kinases receptors work as
dimers
outline how TKs cause cellular signalling
- Dimerization causes autophosphorylation of tyrosine residues on the inside of the channel—> 2nd messenger signalling - Receptors generally work via transducer proteins o Transducer phosphorylation by tyrosine residues o Transducer binds target enzyme and activates
example of Tyrosine kinase receptros
growth factor receptors ANP receptors
ANP receptors
linked directly to guanylyl cyclase
growth factor receptors (TK)
linked directly to tyrosine kinase
give example of ligand of growth facotor receptor ligands
insulin epidermal growth factor (EGF) platelet derived growth factor (PDGF)
When the tyrosine residues are phosphorylated
enzymes (transducers) recongise the complex due to SH2 domain. - Example transducers: IRS-1, Grb2
when insulin binds to its TK receptor
- Insulin binds to the insulin binding domain on the extracellular region of the tyrosine kinase receptor - This causes a conformational change in the receptor- dimerization - Dimerization causes autophosphorylation of tyrosine kinase domain on the inner part of the receptor - Phosphorylated TKs attract transducers o Overall will cause increased transcription of DNA o Increased number of GLUT4 channels
structure of insulin receptor
made up of alpha and beta change linked by disulphide bridge - 2 binding domains - 1 transmembrane domain - 2 tyrosine kinase domains
Membrane bound receptors which couple to effectors through transducing proteins e.g.
G-protein couple receptors
G-protein couple receptors are the
biggest class of receptors
structure of GPCR
- 7 transmembrane domain receptors - Coupled through GTP-binding regulatory protons (G-proteins) to enzymes or channels
G protein is composed of
three subunits: ◦Alpha ◦Beta ◦Gama
example of adrenaline binding to GPCR
• In resting state GDP is bound to the G-protein • Adrenaline comes along and binds causing a confirmation change in receptor • GDP is released from alpha subunit of G-protein • GTP is able to bind to the g-protein • G-protein dissociates • G-protein activates effector • Effector (AC) converts ATP to cAMP (Gs)
how does the steroid receptor work
• Receptors held in silent state by inhibitory protein complex - blocks DNA binding site • When a steroid hormones binds the inhibitory protein is released and the DNA binding site is free
responses to receptor activation can lead to both
cellular activation or inhibition depdneing on the type of receptoer activated
amplification in cellular signalling
binding of a signal ligand to a receptor, can cause a huge reaction within a cell
e.g.
- Activated G-protein (with GTP attached) activates effector enzyme ((AC)
- AC causes ATP–> AMP
- CAMP activates protein kinases
- Protein kinase phosphorylates thousands of enzymes
- Product of enzyme
