Extracellular Signalling Flashcards
Why do cells need to communicate with each other?
- regulate their development and organisation into tissues
- control their growth and division
- coordinate their functions
How do diseases result from at least one breakdown in cell communication?
- the signal may be lost or no longer sent
- the target ignores the signal
- the signal may not reach its target receptor
- there is too much signal
What are the 3 ways in which cells communicate with each other?
- remote signalling
- juxtacrine signalling
- gap junctions
What is remote signalling?
Cells secrete chemicals that signal to cells that are some distance away
What is juxtacrine signalling?
This is contact signalling by displaying membrane-bound molecules that influence cells by direct physical contact
What are gap junctions?
Contact signalling in which gap junctions directly join the cytoplasm of interacting cells
What type of signalling is shown by APCs activating T helper cells?
Why?
APCs display antigen fragments on their cell surface in association with MHC II
The T-cell receptor binds to the antigen on the surface of the APC to activate it
Juxtacrine signalling
How are gap junctions arranged between cardiac myocytes?
Gap junctions form between specialised cells when connexin proteins, expressed by 2 adjacent cells, form a channel
What type of gap junctions allow for rapid electrical coupling between cardiac myocytes?
Connexin-43 gap junctions
What are the 3 stages involved in remote signalling?
- reception
- transduction
- response (intracellular)
What is the difference between the reception and transduction stages of remote signalling?
Reception is receiving an extracellular signal by the cell
Transduction involves transferring the signal from outside the cell to inside the cell
What are first messengers?
What are they secreted by?
They are extracellular signalling molecules
They are synthesised and secreted by signalling cells
How does a first messenger produce a response in a cell?
It produces a specific response in a target cell that has the specific receptor for the signalling molecule
What are the 4 types of intercellular signalling?
- paracrine
- autocrine
- endocrine
- neuronal
What is paracrine signalling?
The signalling molecule acts on nearby cells
What is autocrine signalling?
The cells respond to a signalling molecule secreted by itself
What is endocrine signalling?
The signalling molecule is released into the blood
It can circulate the whole body and act on distant target cells
What is neuronal signalling?
Neurotransmitters being released locally from a nerve terminal in response to a nerve impulse
What are hormones?
Chemical messengers that transport a signal from one cell to another
How is the activity of hormones regulated?
Through positive or negative feedback mechanisms
What is the difference between endocrine and paracrine hormones?
Endocrine hormones are secreted directly into the bloodstream by endocrine glands
Paracrine hormones diffuse through interstitial spaces to nearby target cells
What are hormones involved in regulating?
- the body’s energy needs
- protein and nucleic acid metabolism
- mineral and electrolyte metabolism
- synthesis and release of hormones
What are the 2 main groups of hydrophilic hormones?
- catecholamines
2. peptide hormones
What are the 3 main groups of lipid-based hormones?
- steroids
- thyroid hormones
- sterol hormones (e.g. calcitrol)
What is the difference in the location of the receptor for hydrophilic and lipid-based hormones?
Hydrophilic - receptor is located on the cell membrane
Lipid-based - receptor is located inside the target cell
What does transduction of a signal, after the hormone binds to the receptor, provide?
Specificity and amplification
What are the 4 main classes of receptor?
- ligand-gated ion channel
- G protein-coupled receptor
- receptor tyrosine kinase
- nuclear hormone receptor (intracellular)
What type of receptors are ligand-gated ion channels?
Ionotropic
They are involved in rapid signalling between electrically excitable cells
What happens when a ligand binds to the ligand-gated ion channel?
It causes a conformational change in the channel protein, allowing specific ions to flow through the channel
What is the structure of ligand-gated ion channels like?
They comprise 4 or 5 heterometric subunits surrounding a central pore
How are ligand-gated ion channels different to voltage-gated ion channels?
Voltage-gated ion channels open or close in response to a shift in the membrane potential past a threshold value
What does the nicotinic acetylcholine receptor (nAChR) consist of?
How is it activated?
2a, 1b, 1y and 1d subunits in a pentameric assembly
Each subunit contains 4 membrane-spanning regions
There are 2 ACh binding sites which both must be occupied in order for the receptor to become activated
What is the role of the nAChR when it is activated?
It increases Na+ and K+ permeability
Na+ enters the cell and K+ leaves
What is the composition of a G-protein coupled receptor like?
They are integral membrane protein receptors
It is a single polypeptide with 7 membrane-spanning alpha-helical regions
Each alpha-helical region is connected by alternating extracellular and intracellular loops
Where are the NH2- and COOh- terminus usually located in a GPCR?
The NH2 terminus is on the extracellular side
The COOH- terminus is in the cytosol
What happens when a ligand binds to a GPCR?
Binding of ligands is the result of interactions with the extracellular loop regions, transmembrane domains or combination of the two
How do G proteins interact with GPCRs?
Via intracellular loop 3 and/or the COOH-tail region
What are the targets for GPCRs?
Peptide hormones and neurotransmitters
What is an agonist?
A chemical that binds to a receptor and activates the receptor to produce a biological response
What is an antagonist?
It blocks the action of the agonist by binding to a receptor and preventing a biological response
What happens when a hormone binds to its specific GPCR?
This causes a conformational change of the receptor
This facilitates interaction with a signal-transducing heterotrimeric G-protein
What is the action of the G-protein?
It modulates the activities of downstream effector proteins
These modulate the activities of second messengers that change the activity of the cell
What is a second messenger?
A small intracellular molecule formed transiently in response to receptor activation
What does the RAAS control?
Blood pressure, blood volume and electrolyte homeostasis
What stimulates the RAAS?
- decrease in blood volume
- decrease in blood Na+ concentration
- decrease in blood pressure
What is the role of renin?
It cleaves a decapeptide from the N-terminus of angiotensinogen
This is angiotensin I
What is the role of angiotensin converting enzyme?
It cleaves C-terminal dipeptides from angiotensin I to produce angiotensin II
What other C-terminal dipeptides will ACE cleave?
- bradykinin
- enkephalin
- neurotensin
- substance P
What is the receptor for angiotensin II?
They are GPCRs
There are AT1 and AT2 receptors which are antagonistic
What are the effects mediated by the AT1 receptor?
- vasoconstriction
- increased noradrenaline release from sympathetic nerve terminals
- stimulation of proximal tubule Na+ reabsorption
- aldosterone secretion from adrenal cortex
- vascular growth - hyperplasia and hypertrophy
What types of effects will activation of the AT2 receptor lead to?
Anti-hypertrophic and anti-hypertensive effects
The opposite of AT1
What is hyperplasia?
The enlargement of an organ or tissue caused by an increase in the rate of reproduction of its cells
What types of drugs are used to control RAAS activity?
- inhibiting renin release/activity
- ACE inhibitors
- AT1 receptor antagonists
- aldosterone receptor antagonists
What is the structure of a kinase-linked receptor like?
They have a single transmembrane helix
They have a large extracellular binding domain and an intracellular catalytic domain
What is meant by a kinase-linked receptor being a catalytic receptor?
The receptor itself acts as an enzyme
e.g. tyrosine kinase receptors
What happens after a ligand binds to a kinase-linked receptor?
receptor dimerisation occurs and the receptors are activated
How do kinase-linked receptors act?
They indirectly regulate gene transcription
Where are nuclear hormone receptors found?
How do they act?
they are intracellular and found in the cytosol or nucleus
They regulate the transcription of certain genes
What is the structure of a nuclear hormone receptor like?
They have a monomeric structure with separate ligand and DNA-binding domains
What happens once a ligand has bound to a nuclear hormone receptor?
The cytosolic hormone-receptor complex translocates to the nucleus
It binds to hormone-response elements on the DNA
What are examples of monoamine neurotransmitters?
noradrenaline
adrenaline
dopamine
histamine
serotonin
What are examples of amino acid neurotransmitters?
glutamate
aspartate
glycine
gamma-aminobutyric acid (GABA)
what are examples of peptide neurotransmitters?
endorphins
substance P
neurokinins
neurotensin
What is an example of a lipid neurotransmitter?
anandamide
What are the 5 stages in the lifecycle of a neurotransmitter?
- synthesis
- storage
- release
- receptor activation
- neurotransmitter inactivation
Drugs may act at any of these steps to modulate the action of neurotransmitters
What is involved in the synthesis and storage phases?
Synthesis occurs in the nerve terminal (except neuropeptides)
Storage occurs in synaptic vesicles within nerve terminals
What happens in the release phase?
Neurotransmitters released into the synaptic cleft by exocytosis
This is a Ca2+ dependent process
What happens in the receptor activation stage?
The neurotransmitter diffuses across the synaptic cleft and acts on receptors on the post-synaptic cell
What is involved in neurotransmitter inactivation?
The neurotransmitter is either metabolised by enzymes or taken up into the pre-synaptic nerve terminal
What are the emotional symptoms of depression?
- misery
- pessimism
- low self-esteem
- feelings of guilt, inadequacy, ugliness
- indecisiveness and loss of motivation
What are the biological symptoms of depression?
- retardation of thought and action
- loss of libido
- sleep disturbance
- loss of appetite
What are the two distinct types of depressive syndrome?
Unipolar depression and bipolar affective disorder
What is the main difference between unipolar depression and bipolar affective disorder?
Unipolar depression sees mood swings always in the same direction
Bipolar affective disorder sees depression alternate with mania
What is the role of antidepressants?
To increase monoaminergic transmission within the synaptic cleft
What is the main treatment for depression?
What are the 3 types?
Monoamine reuptake inhibitors
- tricyclic antidepressants
- selective serotonin reuptake inhibtors (SSRI)
- serotonin/noradrenaline reuptake inhibitors (SNRI)
What are the other 4 ways of treating depression?
- monoamine oxidase inhibitors (MAOIs)
- electroconvulsive therapy (ECT)
- mood-stabilising drugs
How do monoamine reuptake inhibitors work?
They bind to pre-synaptic terminal monoamine transporters
They inhibit the reuptake to keep neurotransmitter levels high in the synaptic cleft
How do monoamine oxidases work?
They catalyse the oxidative deamination of monoamines in the presynaptic nerve terminal
This breaks down the neurotransmitters
How do monoamine oxidase inhibitors (MAOIs) work?
They prevent the breakdown of monoamines within the nerve terminal
What are gasotransmitters?
Gaseous molecules synthesised in the body
e.g. nitric oxide, carbon monoxide and hydrogen sulphide
