Lecture 8: How Cells Communicate Flashcards
Why do cells communicate (ceels need, they respond)
Cells need to be able to respond as a cell, and as part of a whole tissue
They respond to signals from other cells and from the environment
Why do cells communicate (these)
These signals are often chemical (but can also be light, taste, smell etc)
Secreted signals can be
long or local distance
Local signaling
Signals act on nearby target cells
Signals act on nearby target cells (growth, neurotransmitters)
growth factors such as fibroblast growth factor – FGF1 (paracrine)
Neurotransmitters such as acetylcholine – ACh (synaptic)
Signals act on nearby target cells (Can act)
Can act on the signaling cell (autocrine)
Long distance signaling
signals act from a distance
signals act from a distance (hormones)
hormones secretes from endocrine cells travel via circulatory ststem to act on target cells
signals act from a distance (hormones eg;)
insulin secreted from pancreatic beta cells enters blood stream & travels and is detected by various body cells.
Cell signaling : Three main steps
Reception, Transduction, Response
Cell signaling : Three main steps (during the transduction)
During the transduction pathway multiple proteins may be activated, typically via phosphorylation
Reception
Signalling protein (primary messenger) binds to a receptor protein
Results in shape and/or chemical state change in the receptor protein
Transduction (altered)
Altered receptor activates a another protein, eg G-protein/adenylyl cyclase
Transduction (The activation)
The activated protein (often an enzyme) may cause a relay of changes
Transduction (Relay molecule)
Relay molecules known as “second messengers”, eg. cAMP, IP3
Transduction (Multiple)
Multiple other proteins may be activated
Transduction (each activated)
Each activated protein causes a series of changes, this is often via
phosphorylation – known as a phosphorylation cascade
Reponse (all, this)
All of the activated proteins cause one or more functions to occur in the cell
This is where the cell actually does something
Receptors are
Specific
Receptors - the human body
The human body will simultaneously send out many different chemicals and molecules, all aimed at eliciting specific responses BUT only the target receptors will interact with that signal (ligand) and use it to activate signal transduction pathways
Where does this specifically come from?
3D molecular shape of the proteins involved
…..structure determines function…..
Receptor - exquisite control is possible (only certain)
Only certain cells at certain times will have particular receptors (ie. dynamic), meaning that while the signal might be widespread the transmission of the signal occurs only where it is needed.
Receptor location (receptors for water)
Receptors for water soluble molecules are membrane bound
eg. G Protein Coupled Receptor, Receptor Tyrosine Kinase, ligand-gated ion channel
Receptor location (receptors for)
lipid soluble molecules are not membrane bound
Can be located in the cytoplasm or inside the nucleus
eg. lipid soluble hormones such as testosterone, estrogen, progesterone, thyroid hormones bind to receptors within the cytoplasm and move to nucleus as a complex
G-protein coupled receptors (GPCRs)
Transmembrane proteins
GPCRs couple with G protein
Transmembrane proteins (pass, hundreds, many, diverse)
pass PM 7 times
Hundreds of different GPCRs exist
Many different ligands
Diverse functions:
eg. development, sensory reception (vision, taste, smell)
GPCRs couple with G protein
G proteins are molecular switches which are either on or off depending on whether GDP or GTP is bound
(GTP: guanosine triphosphate, similar to ATP)
GPCRs
Ligand gated ion channels/receptors (these channel)
These channel receptors contain a “gate”
channel opens /closes as the receptor changes shape
Ligand gated ion channels/receptors (ions)
ions can pass through channel (eg. Na+, K+, Ca2+, and/or Cl−)
Ligand gated ion channels/receptors (binding of ligand)
Binding of ligand (eg neurotransmitter) at specific site on receptor elicits change in shape
Receptor
a molecule/protein which responds to a specific ligand
Ligand
a signalling molecule that binds specifically to another protein
Ion channel
membrane protein through which specific ions can travel
Ion channel receptor
membrane protein through which specific ions can travel, in response to ligand binding (also known as ionotropic receptors)
At rest
ligand is unbound
and gate is closed
Upon ligand binging
gate opens,
specific ions can flow into cell.
Following ligand dissociation
gate closes,
back to resting.
Signal Transduction Pathways
Signals relayed from receptors to target molecules via a ‘cascade’ of molecular interactions
A typical phosphorylation cascade:
Protein kinases
Phosphatases
Protein kinases (are enzymes)
are enzymes that transfer a phosphate
group from ATP to another (specific) protein (kinases phosphorylate). Typically, this activates the protein
Protein kinases (series)
Series of protein kinases each adding a phosphate to the
next kinase.
Phosphate
are enzymes that dephosphorylate (remove
the phosphate) rendering the protein inactive, but recyclable
Single transduction pathways
Typically, it is serine or threonine residues that are phosphorylated.
This means that mutations affecting these residues could be detrimental.
Use of a second messenger - cAMP
Sometimes another small molecule is included in the cascade, these are second messengers.
eg. cAMP and calcium ions
cAMP acts
cAMP acts as a second messenger and activates downstream
proteins, for example, PKA which phosphorylates other proteins
cAMP - the activated, activated
The activated enzyme is adenylyl cyclase
Activated adenylyl cyclase converts ATP to cAMP
Calcium is a widely used second messenger
Low [Ca 2+ ] inside cell (typically ~100nm)
Very high [Ca 2+ ] outside the cell
(more than 1000-fold higher)
Maintenance of concentration
via calciumpumps is important
-out of cell
-into ER
-into mitochondria
Ca 2+ and IP3 in GPCR signalling (here)
Here, the activated protein is
phospholipase C which then
cleaves PIP2 (a phospholipid) into
DAG and IP3
Ca 2+ and IP3 in GPCR signalling (IP3)
IP3 diffuses through cytosol and
binds to a gated channel in the ER
Ca 2+ and IP3 in GPCR signalling (calcium)
Calcium ions flow out of ER down
concentration gradient and activate
other proteins towards a cellular
response
Why so many steps (amplifies, provides)
Amplifies the response
Provides multiple control points
Why so many steps (Allows)
Allows for specificity of response
temporal
spatial
despite molecules in common
Why so many steps (allows for coordination)
allows for coordination with other signaling pathways
Cellular responses include (gene, alteration)
- Gene expression
- Alteration of protein function to gain or lose an activity
Cellular responses include (opening, alteration)
- Opening or closing of an ion channel
- Alteration of cellular metabolism
Cellular responses include (regulation, rearragement)
- Regulation of cellular organelles or organisation
- Rearrangement/movement of cytoskeleton
Cellular responses include (a combination)
- A combination of any of these
Cellular response (the transduction)
The transduction of a signal leads to the regulation of one or more cellular activities
Turning off the response
is important
All of the
signals are for a limited time: activation usually promotes the start of deactivation, so that signalling is of short period of time, ensuring homeostatic equilibrium
it means
the cell is ready to respond again if required
cAMP is broken
down by phosphodiesterase (PDE)
Inhibition
of specific PDE’s can also be a therapeutic approach
eg Viagra - inhibits a specific cGMP-degrading PDE
Example
adrenalin stimulation of glycogen breakdown (adrenalin)
Adrenalin acts through a GPCR, activates cAMP and two protein kinases in a phosphorylation cascade
adrenalin stimulation of glycogen breakdown (results)
Results in active glycogen phosphorylase which can
convert glycogen to glucose 1-phosphate
adrenalin stimulation of glycogen breakdown (amplification)
Amplification means that 1 adrenalin molecule can
result in 108 glucose 1-phosphate molecules!
Glycogen
is a long term energy store in liver and skeletal muscle
Glycogen breakdown
results in glucose 1-phosphate
Glucose 1 phosphate
is then converted to glucose 6-phosphate which can
then be used in glycolysis to generate ATP
Angiotensin-converting enzyme 2 (ACE2)
is
the cellular receptor for the coronavirus
(SARS-CoV-2)
