Receptor Mechanisms I, II & III Flashcards
What is the significance of receptors?
Without receptors the cells can’t produce any biological responses
Where is Ach produced?
Motor nerve produces ACh and stores it in vesicles
How are different biological responses produced via same chemicals?
The same chemical can produce carious biological responses in different tissues depending on the receptor mechanism
What hormones cause blood vessels to constrict?
NA, angiotensin II and thromboxane all stimulate different receptors but all constrict blood vessels
How does the β₁ adrenoceptor cause an increase in heart rate?
- Nor Adrenaline binds to β₁ adrenoceptor
- Increases adenyl cyclase activity
- cAMP levels increased
- PKA phosphorylates Ca2+ channel, activated by cAMP
- Greater influx of Ca2+
- Increased pacemaker, contraction increases
What is the effect of the activation of Growth Factor receptors?
Causes the activation of a receptor kinase leading to the activation of multiple signalling pathways
In biological terms what is a ligand?
A chemical activator
How is the JAK/STAT signalling pathway activated?
By growth hormones
How does an Insulin receptor differ from other Receptor Kinases?
Receptor kinases consist of a single transmembrane domain
Insulin consists of 2 (2a and 2b)
How is the Neuromuscular synapse adapted for fast responses in skeletal muscle?
- short distance between nerve and muscle for Ach to
cross - Abundance of Ach receptors on postsynaptic
membrane
Summarise the Enzyme linked signal transduction pathway
PATHWAY: Enzyme linked
TRANSDUCTION MECHANISM: Conformational change &
phosphorylation of G
protein
EFFECTOR: Proteins with SH2 domain
INACTIVATION: Phosphatase
What is the effect of Ach on blood vessels?
Although Ach contracts skeletal muscles, it relaxes blood vessels using the same type of M3 receptors
Describe the structure of an insulin receptor
Consists of 2a and 2b subunits linked by disulphide bridges
Describe the structure of a Ligand gated ion channel
Has a ligand binding site
Aqueous pathway present
5 proteins make up LGIC (pentameter protein)
form cavity in middle - ionic pathway
- each protein has 4 transmembrane domains
- each LGIC made up of (5x4) 20 proteins/domains
What is the effect of stimulated β₁ adrenoceptor?
- increases force of contraction
- increases contraction rate
Describe the structure of GPCR
- 7 transmembrane domains
- consists of 1 protein only
On 1st TM domain an α subunit (different to LIGC) is bound to a GDP molecule as well as ɣβ subunits joined at the top
G-proteins = αɣβ
What is the function of RAS?
Involved in transmitting signals within cells by activating GDP –> GTP via GTPase activity
Causes: Growth
Differentiation
Cell Motility
Name the 2 GABA receptors that cause hyperpolarisation
- GABAₐ receptors (Cl-)
- Glycine receptors (Cl-)
these receptors have a different TM domain #2
What is the function of Phospholipase C enzyme?
Digests phospholipids especially Phosphotidylinositol biphosphate (PIP₂)
PIP₂ -> IP₃ + DAG
Phosphatidylinositol biphosphate –> Inositol triphosphate + Diacylglycerol
What is the effect of an activated Ligand gated ion channel?
The direct opening of an ion channel upon binding with an agonist
- super fast response
Summarise the Inositol P pathway
PATHWAY: Inositol P
TRANSDUCTION MECHANISM: Conformational change in
G protein
EFFECTOR: Phospholipase C
INACTIVATION: GTPase phosphorylation
What are the types of muscarinic AchR in humans?
In adults - δ 𝜺
In foetal - ɣ α
In neonatal - α β only
Where are insulin receptors found?
Act on liver and muscles to reduce blood glucose levels via tyrosine kinase activity
Outline the process of Tyrosine Kinase Receptor Activation
- Activation of tyrosine kinase receptors activates multiple
pathways
- Dimerisation causes phosphorylation of tyrosine motifs
- Phosphorylated motifs recognised by other proteins
(e. g. GRB-2 recognises SH2 domain) - Undergoes conformational change
- Causing interactions with KASGEF protien
- KASGEF activates KAS and recongises SH3 domain
- This activates proteins which interact with PIP₂ on
membrane - PIP₂ phosphorylated –> PIP₃
- PIP₃ recognised by other kinases (e.g. PDK-1)
Explain how the transmembrane domains in LGIC contribute to the overall structure
The TM domains contain hydrophobic amino acids that contribute to the aqueous pathway
specifically TM domain #2 amino acids make up the ionic pathway
How is an action potential generated?
- Ach binds to LIGC
- Kink formed in LIGC
- Causes influx of Na+/Ca2+
- Cell depolarised
- Excitatory junction potential produced (EJP)
- Causes voltage gated ion channels to open
- action potential produced
What happens when RAS is activated?
- RAS bound to GDP when inactive
- When activated, GDP replaced by GTP by GUanine
nucleotide Exchange Factor (GEF) - GTPase activity occurs
- causing slow dephosphorylation aided by GTPase
Activating Proteins (GAP)
Explain how a cell becomes hyperpolarised
GABA receptors cause anions to move into cell
inhibitory neurotransmitters brought in causing hyperpolarisation
2 GABA bind causing a kink in receptor, allowing Cl- to enter cell
Outline how Ach binds to M3 to contract skeletal muscle
- Ach binds to GPCR M3 receptors
- Activates G₉ α subunit
- Increases Phospholipase C activity
- More Ca2+ channels open - greater influx
- Increased smooth muscle contraction
Give an example of receptor failure
Myasthesia Gravis
- autoimmune disease where muscarinic nAchR are
degraded
- α1 subunits are targeted by antibodies secreted by the
body
(neuronal AchR are unaffected)
How are the phosphorylated tyrosine residues recognised?
Phosphotyrosine and their surrounding amino acids are recognised by SH2 domains on other proteins, allowing them to bind and undergo further activation
What happens when an agonist binds to a GPCR?
- GDP molecule replaced by GTP
- causes α subunit to dissociate from ɣβ
- α subunit interacts with specific enzyme to cause desired effect
- GTP hydrolysed back to GDP
- α subunit reassociated with ɣβ
Name some examples of Growth Factor receptors
- Tyrosine Receptors Kinase
(e.g. Insulin, Epidermal growth factor & Platelet Derived
Growth Factor Receptors) - JAK/STAT
(e. g. Growth hormone, and Interferon receptors) - Serine Threonine Receptor Kinase
(e. g. TGFβ)
How do LIGC produce fast responses?
When an agonist binds to its receptor, an instantaneous molecular kink is formed
- ionic pathway is opened
- allowing ions to flow through
How does the M2 AchR cause a decrease in heart rate?
- AcH binds to GPCR
- Activates G₁ α subunit
- Reduces adenyl cyclase activity
- Decreased cAMP levels
- Less influx of Ca2+
- Reduces pacemaker - heart rate decreased
How does the G₁ α subunit effect levels of cAMP?
G₁ α subunit in GPCR inhibits adenyl cyclase, so cAMP levels reduced
Explain how RAS activity regulated?
- Activated GTPase leads to removal of phosphates
from GTP => GDP - Complex of RAS-RAF breaks down becoming
inactivated - Inactive form waits to be reactivated
Which receptors cause depolarisation?
- Nicotinic receptors (Na+/Ca2+)
- 5HT3 receptors (Na+/Ca2+)
How does Ach binding to M3 cause blood vessels to relax but smooth muscle to contract?
Ach relaxes smooth muscle in blood vessels as the M3 receptors are present on the epithelial cells and not on the muscle itself
What is the effect of G₉ α subunit interacting with Ach on GPCR?
- Activated G₉ α subunit activates phospholipase C (PLC)
- PLC breaks a PIP₂ bond splitting it into IP3 and DAG
- IP₃ binds to its receptor on ER - causing influx of Ca2+
in cytosol - Ca2+ in cytosol bind to Protein Kinase C activating
more PKC and DAG - PKC used for protein phosphorylation causing smooth
muscle to contract
Describe the structure of growth factor receptors
Predominantly single transmembrane domain receptors
Where are the different types of nAchR?
N1/Nm - in skeletal muscle end plates
N2/Nn - in autonomic ganglia in the brain
How is heart rate increased?
Via stimulation of the GPCR, β₁ adrenoceptor
How does Ach cause a decrease in heart rate?
Stimulation of muscarinic AchR M2 in the heart causes decreased contraction and force
as Ach is released from the Parasympathetic Vagus nerve on SAN and AVN cells
causing a decreased heart rate
What processes do enzyme linked receptors help regulate?
- Cell growth
- Division
- Differentiation
- Survival
- Migration
Explain how the LIGC ionic pathway opens up
The internal cavity expands due to the binding of 2 agonists to receptors
There are 2 binding sites in the receptor as 2 agonist molecules are required to bind in order to achieve a full opening of LIGC
Explain how Ach interacts with the Gₛ α subunit in GPCR
- Gₛ α subunit activates adenylate cyclase in cell membrane
- Adenylate cyclase activates cAMP using ATP
- Protein Kinase A (PKA) activated by cAMP
- cAMP degraded by phosphodiesterase
- cAMP acts as a secondary messenger
Explain the effect of insulin binding to its receptor
- Insulin binds to Insulin receptor
- Autophosphorylation of 2b subunits
- Activates IRS family of small protein substrates
- IRS activates RAS and Phospholipase C
What are the symptoms of a pateint with Myasthesia Gravis?
- muscle weakness
- drooping eyelids
- fatigue
- difficulty swallowing/talking
- difficulty in exertion
How are Tyrosine Kinase Receptors activated?
Dimerisation brings two receptor molecules together
Allowing phosphorylation of specific tyrosine residues
(not all tyrosine residues can be phosphorylated)
How can enzyme linked receptors cause cancer?
The inappropriate activation of enzyme linked receptors is associated with disease, particularly cancer
How does depolarisation occur?
When Ach activates a nicotinic receptor, an influx of (cations) Na+ or Ca2+ ions causes the cell to depolarise - cell is excited
Which muscarinic AchR is responsible for decreased heart contraction?
The M2 muscarinic AchR containing G₁ α subunit
What causes fast muscle contraction?
Stimulation of nAchR in skeletal muscle causes muscles to contract quickly
What is the consequence of mutated RAS?
Mutated RAS is found in 30% of human tumours
Why does a healthy membrane potential still fluctuate?
Healthy people have a fluctuating membrane potential due to MEPPs ( miniature end plate potentials) as there is always some Ach binding
What are the 3 main types of α subunits?
Gₛ - stimulates adenyl cyclase
G₁ - inhibits adenyl cyclase
G₉₁₁ - stimulates phospholipase C
How are receptor kinases deactivated?
Dephosphorylation leads to inactivation
What happens when the motor nerve is activated?
- Depolarisation occurs as Na+ channels open
- Causes an influx of Ca2+ ions at postsynaptic membrane
- Acetylcholine released in neuromuscular junction
Where are G protein coupled receptors found?
In muscles - muscarinic receptors
Summarise the cAMP signalling pathway
PATHWAY: cAMP
TRANSDUCTION MECHANISM: Conformational change in
G protein
EFFECTOR: Adenyl Cyclase
INACTIVATION: GTPase phosphodiesterases
Outlie how JAK/STAT signalling pathway occurs
- JAKs cross phosphorylate eachother on tyrosine
- Activated JAKs phosphorylate receptors on tyrosine
- STATS dock on phosphotyrosines (phosphorylated by
JAKs) - STATS dissociate from receptors and dimerise via SH2
domain
How can mutations in key regulatory mechanisms lead to cancer?
Over expression of EGF (epidermal growth factor) can cause breast cancer
due to loss of phosphatase activity
and loss of GTPase activity
What determines the enzyme the α subunit binds to in an activated GPCR?
The specific enzyme the α subunit binds to depends on the type of α subunit present
What is RAS?
Small G protein family member - related to cAMP Gα subunit
How is a slow response produced by AchR?
A slow response is produced by G protein coupled receptors that peak in 10-20 seconds
Outline how Receptor kinases are inactivated
- When the receptor is activated, phosphatases are also
activated - Signalling process sets in motion events that lead to
signal termination - Small G-proteins have intrinsic GTPase activity occur
- Receptor is internalised
Give an example where in the body ligand gated ion channels produce fast responses
Skeletal muscle contraction
Where are GPCR containing G₉ α subunits found?
Present in gut lumen as required for smooth muscle contraction for peristalsis
(wave-like muscle contractions to move food along gut)
Outline the SMAD- dependent signalling pathway
- TGF-β binds to Type II TGF-β receptor causing
dimerisation of the receptor - Dimerisation causes autophosphorylation of
serine/Threonine kinase domain - Acts as a phosphorylation docking site for SMAD 2 and
3 - Phosphorylated SMAD 2 & 3 recognised by SMAD 4
which is also phosphorylated - Complex enters nucleus to bind to specific DNA
regions causing gene transcription
