Case 1 –
1) What are the different categories of cell-cell signalling and how do they function? (Auto-, para-, endo-,
neuro-, exo-, etc. crine)
Cells can respond to physical and chemical changes within the environment, for bacteria and many other
unicellular organisms this can be the basis of quorum sensing to alter their behaviour, but also for multicellular
organisms, cell-cell interactions are the basics for survival. In multicellular organisms the main bulk of mediation
between cells finds place by Extracellular Signal Molecules, and their response depends on the presence of certain
receptors. Activating such receptor will initiate the Intracellular Signal Cascade and will distribute and propagate
the effects onto their target molecules, so-called Effector Proteins. Which can include Transcription Regulators,
Ion Channels, Components of Metabolic Pathways, or parts of the Cytoskeleton.
Many extracellular compounds remain attached onto
the cell of origin and can only activate target cells via
Direct Cell-Cell Contact Dependent interactions, such
as within the immune system. A second mechanism
for interaction is by Mediator Molecules, which are
secreted into the extracellular fluid and can activate
receptors on neighbouring cells: Paracrine Signalling,
or sometimes on the cell of origin itself: Autocrine
Signalling.
To activate targets over much longer distances, cells
might contain long process that allow axons to come
in contact via their target by thin synapses, called
Synaptic Signalling, or requires Hormonal Signal
Molecules secretion into the bloodstream, Endocrine
Signalling.
Extracellular molecules activate specific receptors on the target
cells, these receptors often are composed out of an extracellular
membrane structure, an intracellular compound that propagates
the signal when activated, and the connection between these
parts along the cell membrane. Another method, outside of Cell-
Surface-Receptor activation, is when small hydrophobic
molecules diffuse through the cell membrane that immediately
activate Intracellular-Receptors.
The combination of molecules, be it inhibitory or excitatory,
interacting with receptors of a cell at the same time can induce
many combinatory effects, such as: Apoptosis can be induced
due to Apoptotic Inducing Factors, or due to a lack of Survival
Signals, whereas the latter in combination with Growth factors
can induce cell proliferation, or when mixed with Differentiation
Signals might cause Cell Differentiation.
Another important factor in combining effects, or
rather the huge variety in the response they can
cause, depend on the type of receptor activated, or
the response that is caused as such. Equal
compounds can activate different receptors on
different cell types, but these receptors can also
perhaps be activated by other molecules (agonists)
in certain occasion or inhibited (antagonists), or
cause an altered reaction dependent on the cell
itself, or its state, due to different intracellular
proteins and activated compounds.
,Cell-Surface Receptors most often can be
subdivided into three classes; 1) Ion-
Channel-Coupled Receptors alter the
permeability of the cell membrane to
certain ions and molecules, and therefor
change the excitability of the target cell.
2) G-Protein-Coupled Receptors consist
out of Trimeric GTP-Binding Proteins
(G-Proteins) that mediate the interaction
between activated receptor and the target
protein, which, dependent on the target
protein, might increase certain
enzymatical functions and thus
concentrations within the cells, or might
change the permeability of the cell
membrane if it regards a protein involved
as such. 3) Enzyme-Coupled Receptor
functions as enzymes when activated, or
associate directly with enzymes, to alter
intracellular concentrations by
enzymatical conversions.
Cell-Surface Receptors relay signals via intracellular Second Messenger molecules, which can be small chemicals
such as the water soluble Cyclic-AMP and the fat soluble Diacylglycerol, that pass on the signal by binding to
target proteins. Another type of intracellular signalling molecules are proteins, which can be activated or
deactivated and are sometimes able to produce secondary messengers, or can activate the next signalling or effector
protein.
A large quantity of these proteins are activated by Phosphorylation
via Protein Kinases, and deactivated by Dephosphorylation by
Protein Phosphatases, and hence can be turned on or off. Serine
and Threonine Kinases phosphorylate the hydroxyl groups of
serine and threonine amino acids respectively, whereas Tyrosine
Kinases phosphorylate proteins on their tyrosine. The other
important class of molecular switches is constituted out of GTPase-
Activating Proteins (GAPs), which drive the deactivation of
proteins by increasing the GTP hydrolysis into GDP rate molecule
on proteins, whereas the activation occurs by Guanine-nucleotide
Exchange Factors (GEFs) which remove the afore mentioned GDP
and replace it by GTP.
Outside of phosphorylation, proteins can also be activated due to secondary messengers, by Ca2+ ions, or
deactivated due to ubiquitination, or multiple other alterations. Additionally, to prevent cells from randomly
activating and going haywire, most proteins and receptors are very specific and only have a high affinity for one
sort of molecule/activation system, hence the cross-talk
between multiple pathways is minimized. A second way
to prevent this random activation is the requirement that
often a minimum amount of proteins should be
activated, random activation might occur rather often,
but only due to ‘wanted’ activation of the receptor, an
entire cascade will start that activates more than 50% of
the downstream signalling proteins. These downstream
signalling molecules do not necessarily have to excite
the sequential factor in the cascade, but for example can
also contain a double-sequential-inhibitory step that
increases the activity of further downstream
compounds.
, Large preassembled protein complexes, called Scaffold
Proteins, can help with quickly activating proteins in
response to an activated receptor, but also increase the
specificity of which proteins can dock onto the receptor to
be activated, and as such increase the efficiency and
specificity of the receptors. A second way of this interaction
can be that phosphor groups only attach onto the
intracellular part of the receptor and immediately function as
docking site, and rapidly disassociate when the receptor
deactivates. In another, third, way receptor activation leads
to production of modified phospholipid molecules
(Phosphoinositide) which on their behalf can recruit specific
proteins to be activated.
Activated receptor complexes can also be build out of a
combination of the afore mentioned structures, in which a
docking protein will only bind onto an activated receptor,
allowing it to be activated by phosphoinositide, working
together with Link-Adaptor proteins, that simply can link
multiple protein complexes with one another, which could
include the scaffolding protein. On top of that the proteins
that should be activated might actually be generally
clustered around the receptors itself, or at least within
specific domains encircling the receptors.
The relationship between signal and response can highly differ between specific pathways;
- Response timing can highly differ, whereas neuronal junctions might activate their target within milliseconds,
hormones or morphogens might require hours to days to activate their target.
- Sensitivity is related to the distance between origin and target; hormones tend to activate their target at very low
concentrations and require receptors with a very high affinity as such, whereas short-range neurons can secrete
high levels of neurotransmitters into the synaptic clefts, and allow for much less sensitive receptors.
- The distance between the secretion of the compound and the target can differ from less than micrometres, to half
a metre when it comes to hormones secreted within the brain that travel the bloodstream to affect the kidneys.
- Persistence of the response, partially causal to the extent of positive and negative feedback, can create transient
responses that have a duration of a single second, whereas permanent activation might be required for cell fate
determination.
- Signal Processing also determines how a cell might function, where in one case gradual increase in substances
might cause an abrupt activation, another cell might amplify their signal by positive feedback, or cause oscillations
due to slow negative feedback.
- Some cell types also require activation of multiple receptors by multiple compounds at the same time, which can
allow differences in Integration of Signalling between different cell types.
- Coordination within cells might give raise to one compound and a single receptor activating an entire subset of
consequences, whereas in another case a specific receptor will only cause one specific response in return.
The speed of the response depends on the turnover of signalling
molecules, for one it can alter the proteins that are already present
within the cell, in that case such Allosteric Change can rapidly alter the
structure of a protein and allow for quick responses. When the
activation however is dependent on altered gene expression the
response speed will be much lower, from minutes to hours. Dependent
on the speed at which the produced molecules can be ubiquitinated,
deactivated, or removed in any other type of way, these changes can be
short lasting or be present for extended periods of time, although
theoretically the gene expression alterations allows for longer lasting
cell function alterations than simply altering the proteins present.
, Signal processing can be processed in a smoothly graded Hyperbolic response, as is the
case for many hormones, and can be used to finetune many functions and concentrations
by homeostatic responses, during which proteins slowly increase or decrease their
activity dependent on the concentration. Other signalling systems generate a significant
response only when the molecules reach a specific threshold and are much more abrupt,
which allows for much less specific concentrations, but is less affected by random
noise; sigmoidal. And the Discontinuous or All-or-None response, in which the
response completely switches on when reaching a specific threshold, often irreversible.
These more abrupt changes for example can be produced when the second messengers
are required to bind as bigger groups to their target; the more second
messengers/phosphate groups a protein requires, the sharper the response. Responses
are also sharpened when secondary messengers not simply activate one pathway, but
also inhibit an opposing pathway.
An all or none response can also be initiated by
pathways that heavily induce a positive feedback loop
that allows for a Bi-Stable state, which allows the
proteins to stay activated even after the receptors no
longer have ligands bound, a moderate strength
positive feedback loop in general will fasten the
activation speed and make a stronger sigmoidal
response. Such long lasting changes, when affecting
gene expression, allow for cell memory and
differentiate cells, without of course activating the
genome itself.
Negative feedback on the other hand inhibits its own
protein activation, instead of amplifying it, and can
allow the cell to adapt to certain responses, and as such
slowly decrease its response strength to activation, or
simply allow a very short response regards long-lasting
activation. But secondarily, when the negative
feedback has longer periods of relay, can produce
oscillating signals, which in some cases can initiate
without extracellular activation requirements.
In the case of adaptation the cell can
retract some of its receptors to lower the
rate of responses it produces due to
certain signals, and hence adapt and
desensitise itself, a more long lasting
adaptation would be destroying the
receptors by removing them into a
lysosome. Additional possibilities would
be inactivating a receptor due to negative
feedback of a target protein, or negative
feedback onto a secondary protein
instead of the receptor itself.
Signalling molecules like cyclic nucleotides and calcium are small hydrophilic molecules that generally act within
the cell they are produced, smaller hydrophobic molecules on the other hand sometimes are able to diffuse through
cell membranes and as such might be able to activate cells in a paracrine manner. Nitric Oxide for example can
induce relaxation on smooth muscle cells, produced due to GPC Receptors activating NO Synthases that catalyse
the deamination process of Arginine, and stimulated by Ca2+ ions.
