W7L3 Flashcards
Cells recognize and respond to
environmental cues via receptors
Cells communicate and
coordinate activities by
sending and receiving
signals
▪ Each cell expresses a
variety of receptor
proteins that allow it to
respond to particular
signals.
▪ Signals originate from:
other cells
environment
Environmental signals
- Sensory signalling
Detection of external signals by sensory
receptors for
- Light (rhodopsins)
- Smell (olfactory GPCRs)
- Taste (GPCRs, ion channels, transporters)
- Sound, balance and touch
(mechanoreceptors) - Cellular environment
Cells can detect
- Nutrients
- Protons, pH
- Nucleic acids
- Osmotic pressure (hypertonic or hypotonic solution)
- Fluid sheer stress
- Xenobiotics (chemicals from outside of the body, such as drugs and toxins)
Endogenous Extracellular Signalling Molecules
- Secreted from the signalling cell into the extracellular space
- e.g. hormones, neurotransmitters - Released by passive diffusion through channels in PM
- e.g. ATP, prostaglandins - Liberation of PM-embedded ligands by matrix metalloproteinases
- e.g. growth factors, cytokines - Exposed to the extracellular space, but remain tightly bound to the surface of the signaling cell
- is a transmembrane protein, can bind to receptors on other cells
- e.g. ephrins - Extracellular matrix proteins
- e.g. integrins
Modes of intercellular signalling
- Endocrine signalling
- Paracrine signalling
- Synaptic signalling (a specialized form of paracrine signalling)
- Contact-dependent signalling (aka juxtacrine signalling)
- Autocrine signalling
- Protease-dependent signalling
Endocrine signalling
Endocrine cells release hormones into the bloodstream or lymphatic system - transported throughout body (signalling over long distances)
Hormones act on target cells that express a receptor for the ligand
Examples
- Insulin released from the pancreas promotes glucose uptake throughout the body
- Parathyroid hormone (PTH) is secreted from the parathyroid gland and acts on PTH receptors in bone, kidney, and intestine
Hormone signalling is relatively slow compared to other modes
Paracrine signalling
Para = near
Secreted signalling molecules act as local mediators that impact target cells in the immediate environment
Examples
- platelet-derived growth factor (PDGF)
— wound healing
- locally released parathyroid hormone
related peptide (PTHRP) activates PTH1
receptors in bone and regulates
mineralization
— PTH (parathyroid hormone) is a hormone; PTHRP is a paracrine factor
Synaptic signalling (a specialized form of paracrine signalling)
Regulates neuronal communication
Allows for adaptive changes required for behavioural responses or reflexes
- neurons (nerve cells) extend long axons
- axons contact each other at synapses
- neurons can also form synapses with
muscle cells - rapid mode of signalling
- typically stored in intracellular vesicles
and released into synapses
neurotransmitters include acetylcholine,
catecholamines (dopamine, adrenaline,
noradrenaline), serotonin, endorphins,
GABA, endocannabinoids, corticotropin
releasing factor…
- Can be normal synaptic signalling (presynaptic to postsynaptic)
- Backwards signalling is less common (postsynaptic to presynaptic signal, i.e. cannabinoids)
Contact-dependent signalling (aka juxtacrine signalling)
Physical contact between adjacent cells (or between cell and ECM)
“Ligand” protruding from one cell activates receptor in plasma membrane of neighbouring cell
- ephrin receptors
- adhesion GPCRs
Signalling molecules remain bound to surface of signalling cell
Activate target cells that come into contact with signalling cell
Important in developmental biology
Autocrine signalling
Auto = self
Cell releases a signalling molecule that acts back upon receptors expressed on its own surface to control its activity
Example:
- Cytokine interleukin-1 in immune cells
- Vascular endothelial growth factor (VEGF) in cancer cells
- Neurotransmitters (e.g., noradrenaline, 5HT) which bind to presynaptic autoreceptors
If you block autoreceptors, this will increase the amount of nt
Protease-dependent signalling
Proteolytic activation of precursors
Examples:
- Proteinase-activated receptors: tethered ligand on GPCR aminoterminus is exposed by proteolysis
- Release of membrane-anchored ligand from extracellular surface by metalloproteinase activity
- Conversion of pro-hormone to active form by proteinase activity intracellularly (e.g., endorphins) or
extracellularly (e.g., angiotensin II)
Endogenous ligands can play multiple
signaling roles
Some endogenous ligands can play multiple
signaling roles
i.e. noradrenaline released from adrenal glands travel in blood system and can act as a hormone, a neurotransmitter in the synapse or an autocrine factor by activating pre synaptic receptors
From the perspective of the receiving cell,
what’s the difference between hormonal,
paracrine and autocrine signaling?
How do cells recognize and respond to signals
in their environment?
Cells surface receptors transduce signals into cells
Make a Ligand– receptor complex
Transduce: to convert (something, such as
energy or a message) into another form
–> signal transduction
Affinity
how tightly a drug binds to its receptor
K_D = Koff / Kon
how fast does it go in and come out of the binding site
something that goes in quickly and comes out slowly has high affinity. The lower the K_D, the higher the affinity
Specificity/selectivity
a receptor binds preferentially to ligands that fit well
into its binding site
Saturability
ligand binding is limited by the number of receptors
Reversibility
the ability to bind to and dissociate from a receptor. Most ligands bind reversibly
Competition
a binding site can only accommodate one ligand at a time. If two or more ligands are present they will compete with each other. i.e. agonist vs drug
Agonist
an endogenous ligand or drug that binds to a receptor and promotes activation
Antagonist
a ligand that binds to a receptor but does not activate it
Cellular determinants of receptor signaling
The ways in which different cells responds to a particular agonist may vary:
1.Receptor expression level
- availability of receptors will determine cellular response
- cells that lack receptors for a particular signal cannot respond
- cells with greater receptor density may respond at lower agonist
concentrations and/or activate minor pathways
- Receptor variants
- Ligand may binding to distinct receptor subtypes in different cells - Intracellular signaling components
- same receptor may activate different pathways in different cells
- depends on intracellular factors available to integrate and interpret
receptor signal
- e.g. complement of kinases, ion channels, phosphatases, substrates
Signal turnoff
Endogenous agonists may be
deactivated metabolically
- hydrolysis of acetylcholine by
cholinesterases
- breakdown of peptide and protein
hormones by proteases
Endogenous agonists may be
reabsorbed from extracellular space via
specialized uptake proteins (e.g.,
transporters for dopamine, adrenaline,
noradrenaline, serotonin,
prostaglandins)
Drugs that mimic endogenous agonists can be metabolized by liver enzymes and/or excreted, e.g., via the urine
Receptor activation can also trigger intracellular processes that limit signaling, such as G protein uncoupling and receptor internalization
Molecular Switches –GTP binding and hydrolysis
short term biochemical changes that a cell can undergo to adjust its activity
Heterotrimeric G proteins and small Ras-like G proteins
belong to a superfamily of GTPases where activation and deactivation correspond to GTP binding and hydrolysis, respectively.
For most G proteins, these changes occur on a time scale of seconds to minutes (i.e., slow relative to many
biochemical processes)
Regulation of G protein activation state by other
proteins
▪ GEFs (guanine nucleotide exchange factors) promote
GDP dissociation and thus facilitate activation by GTP
- cells contain 10X amount of GTP as GDP
▪ GAPs (GTPase accelerating proteins) promote the
hydrolysis of GTP, thereby deactivating G proteins
▪ GDIs (guanine nucleotide dissociation inhibitors) inhibit GDP dissociation and thus impede activation
Molecular switches - protein phosphorylation/dephosphorylation
Protein phosphorylation
* ubiquitous strategy
* reversible covalent modification,
with proteins dephosphorylated by
phosphatases
* kinases undergo conformational
changes in response to diverse
inputs, which then regulates kinase
catalytic function (phosphorylation)
ATP cleaved to ADP; phosphate
released covalently attached to a
protein
- Phosphorylation does not
always mean activation
Phosphorylation via kinases. Dephosphorylation via phosphatases
