Cell signaling Flashcards
- Describe principle types of detectors of extracellular signaling molecules.
- List other “tools” of signaling pathways, including at least three 2nd messengers.
- Describe at least three mechanisms for signal termination (including phosphodiesterases).
- Evaluate a “pathway” for amplification and termination.
- Identify “nodes” (such as calcium) and “modules” in a signaling pathway, and evaluate the potential for crosstalk in signal transduction.
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What are the most common types of cell-cell signaling?
1) Contact-dependent cell signaling (Most common in antigen presenting cells of the immune system)
2) Paracrine/Autocrine signaling (Good for short range signaling to neighboring cells)
3) Synaptic Signaling (Good for short distance, fast reaction signaling, as in neuromuscular junctions; Precise, but short-lived)
4) Exocrine Signaling (Good for long distance, slow reaction, as in metabolic regulation; General signaling with long term regulation)
Receptor Types:
1) Ligand (or Voltage)-gated Ion Channels
2) GPCRs (G-protein coupled receptors)
3) Enzyme-linked receptors – including receptor tyrosine-kinases
4) Nuclear receptors – transcription factors activated by cell-penetrating signaling molecules.
Small molecules generated or released within the cell in response to the first messenger, the extracellular signaling molecule. Can bind to intracellular signaling molecules and regulate their activity. Examples (5):
1) Ca2+ enters through ion channels from extracellular space or intracellular stores
2) cAMP (cyclic Adenosine Mono Phosphate) is generated by AC (Adenylate Cyclase)
3) IP3 (inositol triphosphate; released into the cytosol)
4) DAG (diacylglycerol; stays in membrane) are generated by PLC (Phospholipase C)
5) NO (nitric oxide) generated by NOS (Nitric oxide synthase) is cell permeable.
Signaling proteins, activated by receptors or second messengers, can activate other signaling or effector proteins (including enzymes that generate second messengers) in a variety of ways (5).
1) Protein phosphorylation (or dephosphorylation) mediated by kinases (or phosphates)
2) Acetylation (histones)
3) Glycosylation (trafficking through ER, Golgi, etc.)
4) Ubiquitinylation (marking for degradation… and more)
5) Proteolytic Cleavage (of inactive precursors)
In G-proteins coupled to receptors and in small GTPases such as ras. Note that GTP is NOT a second messenger. Why?
Signaling through GTP does NOT depend on its concentration.
What are some properties of Lipophilic (=hydrophobic) signaling molecules?
o can cross plasma membrane – thus, as soon as you make it, it will diffuse out of the signaling cell and go to the target cell
o Can’t accumulate/store it: need to increase transcription to achieve signaling pathway
o Don’t need receptor on the membrane since they can diffuse across
o Very slow response - good for long term regulation as in exocrine metabolic regulation
o Example = steroid hormones
What are some properties of Hydrophilic
(=lipophobic) signaling molecules?
o Hydrophillic molecules
o Can be secreted into the blood stream in large quantities
o Unable to cross membranes: need machinery (vesicles) for secretion o Bind to extracellular receptors
o Able to quickly jack up the concentration of signaling molecules
o High concentrations can be stored in vesicles
o Often used by the nervous system in synaptic signaling
o Examples = growth factors and neurotransmitters
What are some properties of gases as signaling molecules?
o Best known example is Nitrous Oxide (NO) o Used for short range signaling (paracrine)
o Can’t be stored – very short lived
o Can be made very quickly
o Water-soluble
o Can diffuse across membranes – doesn’t require a receptor
Signals can be terminated at any point in a signaling pathway. 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. What are some other ways that signals can be terminated?
1) 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.
2) 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.
3) Protein: phosphorylation or dephosphorylation by kinases and phosphatases to inactivate the cascade mediated by the protein
4) Protein binding/Targeting: protein degradation
!!5) Some enzymes are dedicated to turn off signals (for instance, phosphodiesterases (PDEs) hydrolyze cAMP or cGMP).
Define “nodes” and “modules” in a signaling network.
Nodes are points in a signaling network that have multiple “input” molecular pathways and multiple “output” pathways. For example, 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 also served this function (such as PKA and PKC) that are involved in catalytic reactions of more than one substrate. The result 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 protein complex works as a unit to transduce a particular signal. These are common in feedback mechanisms.
Please discuss PDE5/Viagra with someone who understands it. Thank you.
Please do.
