cell signalling 1, 2, 3 Flashcards
if cells are deprived from cell signaling they will undergo
apoptosis
cell signals conveyed by ______ signalling molecules
extra-cellular
3 stages of cell signaling
1) reception: Signalling molecule binds to cellular receptor, typically on the cell surface
2) transduction: Binding leads to a change in the receptor that triggers a series of actions along a signal transduction pathway
3) response: The transduced signal triggers a specific cellular response
Ligands
signalling molecules; Growth factors, hormones, cytokines & chemical mediators (eg toxins)
receptors
Each cell type displays a set of
receptors that enable it to respond to the ligands (signalling molecules) produced by other cells
Most signalling molecules are _____ & too large to pass through the plasma membrane so they bind to transmembrane proteins called
water-soluble
Surface receptors
some signaling molecules are lipid soluble , what do they bind to
pass through plasma membrane and bind to cytoplasmic or nuclear receptors
Signalling molecules can trigger a change in the metabolism of a cell, give an ex
eg insulin signalling through the insulin receptor
Signalling molecules can trigger a change in the electrical potential across the membrane of a cell, give an ex
eg neurotransmitter signalling in neurons
Signalling molecules can trigger a change in gene expression (transcription) within the nucleus, give an ex
eg adrenaline binding to an Adrenergic Receptor
types of signalling molecules
- Hormones
- Growth factors: Proteins that stimulate cell growth, differentiation
- Cytokines: Small proteins/peptides
- Chemokines: A type of cytokine
- Neurotransmitters
- Neurohormones
- Infectious agents
Endocrine Signalling
- Ligands: hormones
- Long-distance signalling via the blood
Paracrine Signalling
- Ligands: growth factors, cytokines, chemokines & hormones
- Neurotransmitters – special form of paracrine signalling
- Acts locally or over short distances, via the blood or interstitial fluid
Autocrine Signalling
- Ligands: cytokines & chemokines
- Autostimulation; Signalling molecules bind to receptors on the same cell
Juxtacrine (Contact-dependent) Signalling
- Ligands: proteins attached to plasma membrane of cell
- Receptors on adjacent cell
After the ligand binds to the receptor, the receptor interacts with other
intracellular signalling molecules
some cellular responses to cell signalling
changes in:
* Metabolism
* Growth
* Differentiation
* Gene expression
* Secretion
* Structure
(cytoskeleton)
receptors have a high affinity for their
ligands
receptors have specificity for their ligands
Specificity depends on
binding affinity between the ligand & the binding site on the receptor
The affinity between receptors & their ligands is described by the
equilibrium dissociation constant KD
KD quantifies
the equilibrium between a ligand being free in solution or bound to its receptor –> Corresponds to the affinity of a ligand for the binding site on a receptor
KD is the concentration of ligand required for
50% of the surface receptors to be bound by ligand
The higher the KD, the _____ the binding & the lower the affinity.
weaker
Ligands are classified as either receptor ____ or ____, depending on the outcome of ligand-receptor binding
agonists or antagonists
Agonists
ligands that when bound to the
receptor, change the receptor’s activity to produce a response
Antagonists
ligands that when bound to the receptor, do not produce a response
a single receptor may bind
_____ different ligands, and a single ligand may bind to ____ different receptors
several x2
_____ is a neurotransmitter
that is released from the pre-synaptic terminals of neurons
Acetylcholine (ACh)
In skeletal muscle, the ACh receptors are ______
ion-channel receptors aka nicotinic receptors
ACh receptors: can also bind two naturally occurring toxins:
α-bungarotoxin (Taiwanese
Krait, elapid snake) & tubocurare (South American plant)
α-bungarotoxin & tubocurare bind the ACh receptor with _____ than ACh
higher affinity
α-bungarotoxin & tubocurare bind the ACh receptor; how do they work
They bind to the receptor, blocking the binding of ACh, resulting in paralysis of the diaphragm & subsequent death
Transmembrane receptors
cell membrane receptors
that bind ligand outside the cell
Transmembrane receptors: most ligands are
hydrophilic
majority of receptors are
transmembrane receptors
3 types of transmembrane receptors
- Ion channel-linked receptors
- Enzyme-linked receptors
- G protein-coupled receptors
Ion Channel-linked Receptors
- type of transmembrane receptors
- Cation & anion channels
- Involved in rapid signalling events
- Generally found in electrically excitable cells (eg neurons)
- Also called ligand-gated ion channels
Ion Channel-linked Receptors: Transmembrane (integral) proteins have a _____ central canal
hydrophilic central canal (pore)
ion channel-linked receptors; how are transmembrane (integral) proteins open and closed
- Opened and closed by gates
- Conformational change of protein opens or closes the pore via gates
- Opening & closing of gates controlled by binding of ligand
Enzyme-linked Receptors;
type of transmembrane receptors
Either enzymes themselves or are
directly associated with the enzymes they activate
Enzyme-linked Receptors; enzymatic portion is usually
intracellular
enzyme-linked receptors: Majority are
protein kinases, or are associated with protein kinases
Enzyme-linked Receptors
Protein kinase receptors:
* A cell’s response to a signal often involves
activating or inactivating proteins
______ is a common way to change the activity of a protein
Phosphorylation (adding a phosphate group)
Kinases
are enzymes that transfer phosphate groups from ATP to another protein
- Receptor Tyrosine Kinases (RTKs)
type of enzyme-linked receptors
RTKs transfer phosphate groups to tyrosine residues (amino acids)
When the signalling molecules bind to two
adjacent recetor tyrosine kinases (RTKs) ,
they bond together (dimerise)
when Receptors tyrosine kinases are bond together (dimerise) what happens next
type of enzyme-linked receptor
- Phosphates are then added to the tyrosine
residues on the intracellular domain of the
receptors (phosphorylation) - The phosphorylated residues then transmit the
signal to the next messenger in the cytoplasm
enzyme-linked receptors
kinase cascase
- A series of protein kinases that phosphorylate each other in succession
- Amplifies the signal
melanoma: >50% carry mutations in kinases such as BRAF –>
–> constitutive activation –> uncontrolled cell proliferation
G Protein-coupled Receptors
- Transmembrane (integral) proteins
- Also known as Seven Transmembrane
Receptors (7TM receptors) - Coupled to a G protein
ligands of G protein-coupled receptors include
odours, pheromones,
hormones, neurotransmitters, light E,
lipids & sugars
G proteins
Specialised proteins that bind to nucleotides Guanosine Triphosphate (GTP) & Guanosine Diphosphate (GDP)
G proteins have __ subunits
3;
α, β, γ
G proteins: alpha subunit bind
GTP or GDP, depending on
whether the protein is active or inactive
G proteins; in the absence of a signal
GDP binds & the entire G protein-GDP complex binds to a nearby GPCR
When a signalling molecule binds to the G protein-coupled receptor
the GPCR changes conformation & activates the G protein, GTP replaces GDP
Numerous second messengers produced
intracellular receptors; Many small signalling molecules are _____
hydrophobic
intracellular receptors Transported in
blood & extravascular fluids
bound to carrier proteins
how do intracellular receptors enter cell
But are lipophilic so dissociate from carrier protein to enter cell
Steroid hormones, thyroid hormones, vitamin D3, retinoic acid are examples of
intracellular receptors
steroid hormone signalling steps
(intracellular receptors)
- Transported in the blood bound to carrier proteins –> surface of their target cell.
- The steroid drops off the carrier and the free steroid enters the cell.
3a. Some steroids bind to a cytoplasmic receptor which conveys them into the nucleus.
3b. Others do not bind to a receptor until they enter the nucleus. - The steroid-receptor complex is called a transcription factor and by interacting with the DNA alters the expression of specific genes.
signal transduction
After the ligand binds to the receptor, the receptor interacts with other ______
intracellular signalling molecules
second messengers
- Small molecules & ions that relay signals received by cell-surface receptors
- Because they are small, they diffuse rapidly
second messengers are small so they
diffuse rapidly
second messengers examples
- Cyclic nucleotides: cAMP, cGMP
- Ions: Ca2+
- Phospholipid-derived molecules: inositol triphosphate
- Gases: nitric oxide
cyclic adenosine monophosphate (cAMP) is synthesized by
adenyl cyclase enzymes from ATP
describe adrenaline signalling in skeletal muscle
Adrenaline binds to GPCR β-adrenergic receptors –>
G protein activation stimulates cAMP synthesis by adenylyl cyclase –>
cAMP activates protein kinase A –>
activates phosphorylase kinase –>
activates glycogenphosphorylase –> glycogen breakdown –> glucose released into blood
Caffeine enhances the action of cAMP by
inhibiting the enzyme phosphodiesterase (PDE) that degrades cAMP
Each molecule of
adrenaline that arrives
at the cell membrane
results in _____ molecules of glucose in
the blood:
10,000
Ca2+ concentration inside cells much _____ than outside
lower
Many signalling molecules induce
responses in cells via signal transduction pathways that ____
cytoplasmic levels of Ca2+
increase
_____ functions as a
second messenger in G
protein & tyrosine
kinase pathways
Ca2+
what triggers release of Ca2+ from ER
signal transduction
–> cell response
Phosphoinositol Signalling Pathway
- Adrenaline binds to a GPCR –> GPCR changes
conformation & activates the G protein, GTP replaces GDP - The activated α subunit activates phospholipase
C –> hydrolyses phosphatidylinositol 4,5- bisphosphate (PIP2) –> results in the formation of second messengers diacylglycerol (DAG) and inositol-1,4,5-triphosphate (IP3) - IP3 binds to calcium pumps on ER –> Ca2+
released into the cytoplasm –> Ca2+ binds to many proteins, activating a cascade of
enzymatic pathways
Phosphoinositol Signalling Pathway steps summary (6 steps)
1) ligand binding
2) G alpha and RTK activation
3) PLC activation and G alpha and RTK
4) PIP2 –> IP3 + DAG
5) IP3R binding Ca2+ release
6) IP3 phosphorylation by ITP3K
_____ inhibition of the Phosphoinositol Signalling Pathway to treat bipolar disorder
lithium
nitric oxide
free radical that
diffuses across cell membranes
nictric oxide is both
- Both hydrophilic & lipophilic
- Acts in a paracrine or autocrine manner
nitric oxide Plays an important role in many physiological processes including
neuronal signalling, immune responses, inflammatory responses, modulation
of ion channels, phagocytosis, vasodilation…
NO signalling in vasodilation
- ACh binds to the GPCR –> GPCR activates phospholipase C (PLC), which catalyses the
production of IP3 –> IP3 acts on the IP3-
gated Ca2+ channel in the ER –> release of
Ca2+ - Ca2+ binds to calmodulin (CaM) to form Ca2+-CaM complex –> reactivates NO synthase (eNOS) in endothelial cells –> NO produced –> NO diffuses into vascular smooth muscle
cells…smooth muscle relaxation
exosomes
- Membrane-bound extracellular vesicles
- Generated by all cells
- Contained within multivesicular bodies
exosomes contain
- Contain proteins, lipids, metabolites, DNA, RNA
exosomes are taken up by cells via
endocytosis, where they affect function
exosomes; what do they do, what are they involved in
- Associated with pathogenesis of cancer,
inflammation, neurodegeneration… - Likely involved in cell-cell communication
- Proteins, metabolites & nucleic acids delivered into recipient cells alter their biological response
- Exosome-mediated responses can both
promote & suppress disease progression
exosomes ar engineered to deliver
therapeutic payloads,
including chemotherapeutic agents, immune modulators…
exosomes have potential to aid in
disease diagnosis
what fluids are exosomes present in
Present in all biological fluids: makes them easy to sample in liquid biopsies
