Cell Signalling Flashcards
Toolbox
- ) Receptors
- ) Intracellular signaling mediatiors
- ) Target proteins (metabolic enzyme, gene regulatory protein, cytoskeletal protein, exo/endocytosis protein)
Receptors
May be named after their natural ligand or a pharmacological one
Types:
Ligand (or voltage) gated ion channels
GPCRs
Enzyme linked (receptor tyrosine kinases)
Nuclear receptors
Metabolic sensing? non-receptor mediated
Second Messengers
Signaling depends on concentration.
Generated or released within cell in response to first messenger. Can bind intracell signaling mlcs and regulate their activity.
Ca: enters through ion channels from ECM or intracell stores
cAMP: generated by adenylate cyclase (AC)
IP3: inositol triphosphate, released in phosphate and DAG: diacylglycerol stays in membrane… generated by PL
NO
Protein modification
Phosphorylation, acetylation, glycosylation, ubiquitnylation, proteolytic cleavage (of inactive precursors)
Protein Protein Binding
Can directly regulate activity/ target a signaling protein to specific locations.
Targeting often involves protein-protein binding.
Can regulate by promoting access to nearby downstream substrates or preventing access to others.
GTP/GDP exhange
G-proteins coupled to receptors and in small GTPases.
GTP IS NOT A SECOND MESSENGER b/c signaling through GTP does NOT depend on its concentration
When can a signal be terminated?
At any point in a singaling pathway. Extracellularly. signaled by another signal. By enzymes Some have built in terminators (like ras)
Amplification
one upstream activates more than one downstream, can cause further amplification
Amplification depends on?
Time it takes to terminate activity of a signaling molecule (beyond the upstream signal?)
How many downstream target mlcs affected?
Example of amplification?
Positive feedback loop (sig 1 enhances sig 2 which enhances sig 1)
Often coupled with negative feedback to keep control
Network causes?
Cross-talk
Coincidence detection
Simultaneous activity (or non-activity) of several receptor types may be needed to get a signaling outcome. 2 may block 1, 2 may be necessary for 1, 2 may modulate 1
Why use some connections in a network not others?
- ) Some may require add’l input
- ) Signaling protein may not be expressed in that cell
- ) Wrong location of expression
- ) Activated but downstream path doesn’t lead to fx.
- ) Fx. results that we don’t care about
Node
Point in a network that receives multiple inputs and/or mulltiple outputs
Calcium is a good example.
Modules
Groups of components that fx. together. Often physically associated into complexes.
No rigid defintions.
Autocrine
self-stimulation (Receptors on signaling cell)
Paracrine
Release signaling mlc that neighboring cells have receptors for
Contact-dependent
Signaling mlc not released
Endocrine
far away, into blood stream, relatively slow
2 major classes of singaling molecules?
- ) Lipophilic
2. ) Hydrophilic
Lipophilic signaling mlcs.
ex: steroid hormones, yes penetrate mem. Receptor can be intra-cellular. No cell storage possible. Control of release? Only by synthesis Speed? slow
Hydrophilic signaling mlcs
ex: peptides/proteins/AA's do NOT penetrate mem (makes sense...) Receptors have to be on cell surface (also duh) Yes can have cell storage (vesicles) Control of release? via vesicle release? Speed? FAST
Termination examples
Extracell signaling mlc: degraded, diffuses away
Receptor: desensitization, internalization
2nd messenger: pumped away
Phosphorylation….dephosphorylation
Protein binding: get rid of cmplxs. degrade,
Termination mediated by?
Constitutively active terminators (Ca pumps, phosphatases)
Signal induced terminators (phosphatases, GAP)
neg feedback (ca pumps)
most termination events can be modulated by signaling
PDE5
Shows cooperativity. Enhanced binding, has catalytic site for breakdown.
Consequence of cooperativity?
Activity response is over a smaller concentration gradient (sharper response)
