Cell Signalling 1 Flashcards
Define Signal Transduction.
= process of transforming one form of a signal into a different message, more understanable for the further processes
- signalling cell -> sends a message in a form of extracellular signal molecule -> recognised by receptors on the target cell -> converted into intracellular signalling molecules -> change in cellular behavior
What types of extracellular signal molecules can you name (4)? What cells emit/use those or what is their function?
- Hormones - most wide-spread, send through bloodstream
- secreted by endocrine cells e.g. pancreas -> insulin
- Local mediators - paracrine signalling
- signals diffuse locally in the extracellular space -> affect only nearby cells
- involved in regularion of inflammation, wound healing
- specific type = autocrine signalling = cells respond to their own mediators e.g. cancer cells can promote their own growth
- Neuronal/synaptic signalling
- Contact-dependent (cell-to-cell)
- no release of molecules, just direct contact of plasma membrane proteins
- usedin embryonic development allowing adjustent cells to become specialized
Cells are constantly exposed to hundreds of signals diffused within the extracellular fluid -> how come they don’t all react to it and perform the same actions?
In order for a cell to respond it needs a specific receptor - which tends to react only to one type of signal
Still evenwith just one signal cells can produce all kinds of responses (changes in movement, shape, gene expression) - all thanks to specific signalling pathways and their effector proteins
- (different types of cells can respond to the same signal differently)
=> All depends on how the cell receives and interprests the signal
True or False: “Cells adjust their behavior one signal at a time (i.e. one signal = move, another = divide)”
False. The cell can orchestrate sequence of interactions from different signalling pathways - usually a result of those specific pathways and their timings determine what behavior will be displayed
True or False: “All cellular behaviors can be derived within seconds to minutes”
False. We indeed do have fast cellular responses that utilize already existing proteins/machinery e.g.contraction of muscle cells upon acetycholine signal.
However, there are also reactions that take number of hours to be executed (since they might require gene transcription) e.g. cell growth, proliferation
What 2 classes of extracellular signal molecules do we have?
- Molecules that are too large or too hydrophillic to cross the plasma membrane -> they rely on cell-surface receptors
- Molecules small enough or hydrophobic pass through and bind to intracellular enzymes/receptors
Name an important family of small, hydrophobic signal molecules - what is the principle of their function?
Steroid hormones
- e.g. cortisol, estradiol, testosterone, thyroid hormone
-> enter a cell and find in cytosol or at nucleus - nuclear receptors (= r. that upon hormonal binding activate gene transcription)
- under normal circumstances present in inactive state
-> once binding occurs ->conformation change = active => promoting or inhibiting transcription
NOTE: each hormone binds to a different receptor, acting on different set of genes in different cellular types
Some dissolved gasses can cross the plasma membrane - name one and explain (one of) its function(s) in the body.
Nitrid Oxide - synthesized from amino acid argenine -> diffusing over
- acts on nearby cells, otherwise converted into nitrates or nitrites by pairing up with O2 or H2O
- Function: endothelial cells forming the lining of blood vessels release NO upon neural signal -> acts on smooth muscle cells -> relaxes them -> blood vessel dilation
NOTE: used in medicine to treat angina = pain caused by inadequate blood flow
How can NO be involved in intracellular signalling? How does it work in the case of Viagra?
Inside many cells NOcan bind to and activate enzyme Guanylyl cyclase -> stimulates formation of cyclic GMP from nucleotide GTP -> signalling for next cell response
Arousal -> PNS activates -> signal travels via pelvic sphantic nerve -> pelvic plexus -> stimulate corpus cavernosum with acetylcholine -> endothelial cells synthetize NO from arginine -> NO released -> enters endothelial cells -> activates Guanylyl cyclase -> conversion of GTP into cyclic GMP -> muscle relaxation -> blood vessel dilation => erection
Viagra inhibits phosphodiesterase type 5 (PDE5) that should break down cGMP => erection lasts for longer
What are the crucial functions of intracellular signalling pathways?
- Relay signal onwards
- Amplify the signal
- Integrate signals from multiple pathways
- Distribute the signal to more effector proteins
How are these functions modulated?
Feedback regulation
- positive = downstream component acts on the earlier one to enhance the initial signal
- negative = downstream component inhibits the earlier signal to decrease the initial response
What is meant by molecular switches?
= intracellular signalling proteins that exist either in inactive or active state
- just like there is a mechanism swithing it off there HAS to be mechanism to switch it off again
Name one class of molecular switches (the largest one)? On what mechanism does it function?
Proteins that are activated or inactivated by the means of phosphorylation
- one switch done thanks to Protein Kinase = adds phosphate group
- second switch relies on Protein Phosphotase = removes a phosphate group
=> Activity of any such protein depends on the balance of these 2 enzymes
What is meant by phosphorylation cascade? What two types of kinases operate in intracellular signalling?
= one protein kinase phosphorylates the next protein kinase phosphorylates the next
- Serine/threonine Kinases, Tyrosine Kinases
- named after the side chain group that receives the phosphate group
What is the second class of molecular switches?
GTP-binding proteins = switch is made depending on the presence of GTP or GDP
- once activated by GTP binding, the protein uses its intrinsic GTPase hydrolizing mechanism to shut itself down by removing one phosphate group again (GDP)
What are two types of GTP-binding proteins?
- Trimeric DTP-binding proteins (also called G-proteins)
- Monomeric GTPases
- aided by two sets of regulatory proteins: guanine nucleotide exchange factors (GEFs) which promote the conversion of GDP->GTP
and GTPase-activating proteins that turn it of by promoting GTP hydrolysis
- aided by two sets of regulatory proteins: guanine nucleotide exchange factors (GEFs) which promote the conversion of GDP->GTP
Cell-surface receptors fall into 3 main categories - what are those?
- Ion-channel-coupled r. = change permeability of plasma membrane to specific ions -> change in membrane potential
- G-protein-coupled r. = actives G-proteins that act on ion channels or effector proteins leading up to more downstream effects
- Enzym-coupled r. = activate enzymatic activity of certain signalling pathways
NOTE: signalling molecules can act on multitude of these e.g. nicotinic r. X muscarinic r.
Look at the table of foreign substances:
What is the general structure of a G-protein-coupled receptors (GPCRs)? Can you give example?
- Made of a single polypeptide chain that threads back and forth across the plasma membrane - specifically 7 times
= Seven-pass transmembrane receptor proteins
E.g. rhodopsin, muscarinic receptors
How in general do G-proteins work?
Although there are several types each reacting to a specific set of signals and affecting particular effector proteins - there are some similarities
Composed of 3 subunits - alpha, beta, gamma (two of which are bound to the membraneby a lipid tail)
- when unstimulated alpha holds GDP
-> Once signal comes -> conformational change -> lower affinity of GDP at alpha -> gets released and immediately replaced by GTP (high concentration in cytosol)
-> (in some cases:) alpha+GTP detaches fromb beta+gamma complex -> each free to interact with different molecules
-> after a while interna GTPase inside alpha hydrolyzes GTP into GDP -> returns back and reunites
NOTE: The longer units stay bound to target proteins -> the longer the response will last
How is the disease Cholera connected to G-proteins?
Bacterium of cholera multiplies in the gut -> produces cholera toxin -> enters the cells of intestine lining and acts on the alpha subunit of Gs (which normally stimulates activity of adenylyl cyclase) -> prevents alpha from hydrolizing GTP -> constant activation
-> constant outflow of Cl- and water into intestines -> extreme diarrhea, dehydration (helps bacteria to move from host to host)
What about whooping cough (pertussis)?
Bacterium multiplies in lungs -> produces pertussis toxin -> inhibits Gi (locks it in inactive state -> constant activation of adenylyl cyclase -> constant coughing
How does the G-protein related to slowing down the heart beat work?
Acetylcholine of PNS activates muscarinic receptors -> activation of Gi -> beta/gamma complex detaches -> binds to K+channels -> holds them in open position => becomes harder to generate action and contract the muscle
- once alpha hydrolysis all is returned back and K+ channels can close again
What are the two most common enzyme targets of G-proteins? And what do they produce?
- Adenylyl cyclase
- second messenger = cyclic AMP
- Phospolipase C
- second messengers= inositol triphosphate (in turn raises Ca2+ concentration), diacylglycerol
NOTE: each are activated by different types of G-proteins -> but can interact and create more diverse complex responses
