cell signaling Flashcards
Detectors are the receptors, generally on the outside of the cell or organelle responsible for
recognizing a given signal.
There are 6 major classes of detectors.
- voltage dependent ion channels
- ligand dependent ion channels
- G protein coupled receptors
- Enzyme linked receptors
- nuclear receptors
- metabolic sensing
voltage dependent ion channels,
like Na channels and Ca channels, that sense a given voltage to change conformation.
Ligand dependent ion channels,
like acetylcholine nicotinic receptor, recognize a specific molecule or set of molecules.
G-protein coupled receptors,
like the muscarinic acetylcholine receptor, recognize a ligand and interact with a G-protein.
Enzyme linked receptors,
like the serine/threonine kinases, have enzymatic activity associated with ligand binding.
nuclear receptors that
are often transcription factors and regulate gene expression directly, such as steroid hormones.
metabolic sensing,
which is not really a receptor mediated signaling pathway. However, metabolic changes can cause signal pathways within cells, as in glucose-induced depolarization of pancreatic beta cells.
Other tools of cell signaling include
second messenger, which are molecules that relay signals from a receptor to target molecules in the cell.
A few important second messengers are
- Ca2+
- diacylglycerol (DAG) in the membrane
- inositol triphosphate (IP3) in the cytoplasm
- cyclic adenonsine monophosphate (cAMP)
- cyclic guanosine monophosphate (cGMP)
- nitric oxide (NO) a gas capable of permeating other cells.
In addition to second messengers, other tools involved in signaling include:
- Protein modification (phosphorylation, acetylation, glycosylation and more)
- Protein-protein binding and protein targeting responsible for localizing proteins where they need
to function - GTP/GDP exchange used by G proteins and small GTPases
Nearly any step in the cell signaling cascade can become a site for ____. This action results in the ______
termination
stopping of the signaling cascade.
Extracellular signaling molecules:
can diffuse away from the cell, become inactive, or all be taken into the cell, preventing their ability to signal on the surface.
Receptors: can become
desensitized and fail to bind to present ligand, reduction of binding or downstream signaling by the receptor, and internalizing the receptor so it cannot respond to extracellular signals.
2nd Messengers:
can be pumped out of cells or into storage sites, prevented from functioning by cleavage of cAMP and cGMP to AMP and GMP respectively by phosphodiesterases.
Protein: phosphorylation or dephosphorylation by kinases and phosphatases to
inactivate the cascade mediated by the protein
Protein binding/Targeting:
protein degradation
Signal termination is often modulated by the
signaling that it is involved in, i.e. negative feedback loops, constitutively active terminators (that are never off, such as phosphodiesterases) and signal induced “terminators” such as phosphatases and GTPases.
Amplification occurs when
a molecule in a cascade activates more than one of the next molecule in the cascade.
Any system where there is a ration of
greater than one to one of receptors to effectors uses some sort of amplification.
Amplification can occur at the level of
channels and receptors, second messengers, transducers or effectors.
Nodes are
points in a signaling network that have multiple “input” molecular pathways and multiple “output” pathways.
Node examples
Ca is a second messenger in many pathways, but not all the pathways modulated by Ca are activated every time Ca is released.
Multifunctional enzymes can function to:
(lPKA and PKC) that are involved in catalytic reactions of more than one substrate.
The result of multifunctional enzymes is that
there can be extensive communication between pathways, resulting in “cross talk” or many signaling events resulting from a particular ligand binding.
Modules are protein complexes that:
process signals together
The Module protein complex works as a unit to
transduce a particular signal.
Module protein complexes are common in
feedback mechanisms
other signaling steps include
- protein modification
- protein-protein binding
- GTP/GDP exchange
Protein modification
examples
- Protein phosphorylation (or dephosphorylation) mediated by kinases (or phosphates)
- Acetylation (histones)
- Glycosylation (trafficking through ER, Golgi, etc.)
- Ubiquitinylation (marking for degradation… and more)
- Proteolytic Cleavage (of inactive precursors)
Protein-Protein Binding (and Protein Targeting) can directly
regulate activity and/or target a signaling protein to specific cellular locations.
Protein targeting often involves
protein-protein binding, but can include other mechanisms as well.
Protein targeting can regulate
signaling enzymes by promoting access to nearby downstream substrates, and by preventing access to other substrates.
GTP/GDP exchange is seen in
In G-proteins coupled to receptors and in small GTPases such as ras.
Note that GTP is NOT a second messenger, because
signaling through GTP does NOT depend on its concentration.
amplification and termination occurs in
every signaling pathway
A signal can be terminated at any point in a signaling pathway, starting with the
extracellular signaling molecule (which can be taken up into cells and reused; broken down extracellularly; or simply diffuse to reach a too low concentration).
Termination of a signal can be initiated by
another signal (for instance, phopshorylation by a kinase can be reversed by dephosphorylation by a phosphatase).
Some enzymes are dedicated to
turn off signals (for instance, phosphodiesterases –PDEs- hydrolyze cAMP or cGMP).
Some signaling proteins have built in
terminators (G-proteins and ras-like proteins are slow GTPases, thereby reversing their active GTP-bound state).
a positive feed-back loop is usually coupled with a
negative feed-back loop that stops the signal before it gets out of control.
Nodes are points in a network that
that receive multiple inputs and/or multiple outputs.
most extensive node in signaling?
Ca2+
modules are groups of
components that function together.
In signaling there are often proteins physically associated to form complexes
Signal Amplification types
- Amplification Hormones:
2. Photodection:
amplification hormones
Low concentration, large effect
Photodection:
Measurable effect of a single photon
that does not mean that we can actually “see” a single photon!
Amplification by:
- positive feedback
2. signaling cascades:
positive feedback
(Ca2+ induced Ca2+ release)
usually coupled to a negative feedback loop
signaling cascades: amplification depends on
- how many downstream target molecules affected?
- how long does a signaling molecule remain active?
(beyond the upstream signal?)
Signal Termination
- Extracellular Signaling Molecule
- Receptor: Desensitization
- 2nd messenger
- Phosphorylation
- Dephosphorylation
- Protein Binding/Targeting
Signal termination:
Extracellular Signaling Molecule:
- Diffusion;
- Inactivation;
- Uptake into Cells (by Transporters; can be important drug targets; for instance Dopamine Transporter)
Signal termination:
Receptor:
Desensitization:
- Reduction of Binding or downstream signaling;
2. Receptor internalization (often “plasticity” event affecting subsequent signals)
Signal termination:
2nd messenger:
- Ca2+: ATP dependent pumps; out of cell or into stores
- metabolic modification:
- -cAMP or cGMP to AMP or GMP by PDEs
Signal termination: Phosphorylation
phosphorylation-> dephosphorylation by Protein Phosphatases
Signal termination:
dephosphorylation
Dephosphorylation -> rephosphorylation by Protein Kinases
signal termination :
Protein Binding/Targeting:
Lack of the inducing stimulus; protein degradation
Signal Termination
Termination mediated by:
- Constitutively active “Terminators”
- Signal induced “Terminators”
- Negative Feedback mechanism (Ca2+ pumps)
Constitutively active “Terminators” examples
(Ca2+ pumps; PDEs; 2. Phosphatases; intrinsic GTPase)
Signal induced “Terminators” examples
(Phosphatases; GAP enhanced GTPase)
most termination events can be at least modulated by ____
signaling
Networks:
Extensive potential for communication between pathways
Pathway through a node:
multiple inputs or outputs
2nd messengers
multifunctional enzymes
Pathway through a module
process signals together
signal protein complexes
feedback mechanisms
