Cell Signaling Flashcards
_ channels
plasma membrane or organelle, signal by opening ion gates, drugs can affect synaptic transmission at different loci, liberation of Ca++ stores will have profound effect on cells
ligand activated ion channels
_ receptors
adenylate cyclase and the pleotrophic effects of PKA; Phospholipase A2 and the liberation of arachidonic acid; phospholipase Cbeta and signaling by IP3 and DAG
receptor desensitization
G protein coupled receptors
G protein cycle
Galpha effectors - adenylate cyclase
_ receptors
receptor dimerization, phosphorylation, docking of effectors MAP kinase cascade-transcription factor activation, JAK-STAT pathway
tyrosine kinase receptors
_ receptors mechanism of action: class one and class 2 nuclear receptors
ligand activated nuclear receptors
hormonal activation of liver phosphorylase is mediated by _, a second messenger, the hormone is the first messenger
cAMP
phosphorylase is regulated by phosphorylation by _ enzymes
kinase enzymes
kinase cascade
about 40% of all drugs are directed agonists or antagonist of one or another _ receptor
g protein coupled receptor
_ receptors
signaling in excitable cells , important in concept of pain
multisubunit proteins
produce graded potential (effects are local)
depolarizing - let in Na+(usually not particularly selective), examples?
hyperpolarizing - let in Cl- making harder to reach the AP, examples?
ligand-activated ion channels - plasma memrane edition
excitable cells like skeletal muscle
depolarizing - Ach, serotonin, glutamate
hyperpolarizing - glycine, GABA
activating and inhibiting ligand activated plasma membrane ion channels is the basis of synaptic transmission of _
nerve impulses
plenty of drugs targeted here
some drugs might mimic or block the actions of neurotransmitters to affect synaptic transmission
some drugs might block the channel to affect the synpatic transmission
Sometimes enzymes inactivate NT and sometimes receptors on the presynatpic reuptake
Never want the postsnapatic to get NT after shit has already happened
some drugs might affect NT metabolism
which kind of receptor
lingand activated channel plasma membrane
_ receptor
IP3-mediated Ca++ release from the ER
inositol 1,3,5 bis-phosphate
this receptor mediated Ca++ release from the ER internal store “puffs” of Ca++ alters cell physiology
ligand-activated ion channel organelle edition
_ receptor
single polypeptide 7 transmembrane alpha helices
800 functional genes encode this receptors
400 in your nose
too many ligands to mention
G protein coupled receptors
agonists bind to the GPCR’s alterr the proteins confirmation, leading to the activation of a _ g protein
- Ligand bound GPCR stimulates _ exchange
- the causes the complex to fall apart into two pieces _ and _
- the _ has an intrinsic GTPase activity. Eventually the GTP is hydrolyzed to GDP and Pi. RGS proteins accelerate this process
- After _ hydrolysis the complex reassembles
trimeric G protein
3 subunits alpha, beta, gamma
- GDP-GTP exchange
- Galpha and GbetaGgamma
- Galpha
- after GTP hydrolysis the complex reassembles
Beta and gamma together can affect shit and then alpha by itself
The signaling system is designed to shut itself off. Doesn’t keep signally on and on - it shuts up by itself
The G protein cycle
major - the liberated G_protein
minor - the liberated G_ protein
bind to and activate proteins in the cell
major - the liberated Galpha protein
minor - the liberated GbetaGgamma protein
plays a role in signaling, but not as important
the G protein cycle
major - the liberated Galpha protein
effects _ to take ATP and converts to cAMP
adenylate cyclase
Galpha > ATP >adenylate cyclase> cAMP + PPi
cAMP - protein kinase A - phosphorylation of a large number of proteins producing a large number of biological effects
protein kinase - catalytic tetramer
cAMP goes up - regulatory subunit
G protein receptors
phosphorylation of transcription factors by PKA and other protein kinases can lead to changes in _
in gene expression in cell
PKA mediated activation of glycogenolysis (mobilization of glcuose) in the liver is an example of what kind of receptor
g protein coupled receptors
major effectors of Galpha’s
signaling molecules are embedded within phospholipids in the membrane, and G protein coupled receptors liberate them by activating _
phospholipases
phospholipase A2, C, D
which phospholipase in the G protein receptor cycle liberates arachidonic acid
phospholipase A2
arachidonic acid is the source of _ signaling molecules
Eicosinoids
prostaglandins - important signaling molecules and mediators of pain and inflammation
major effectors of Galpha’s - phospholipase Cbeta
products of PLCbeta mediated hydrolysis are _ and _ both are important signaling molecules (minor) that liberates calcium from the sarcoplasm reticulum
DAG (diacyl glycerol) and IP3 (3,4,5, triphosphate
cleavage of PIP2 by phospholipase C yields DAG and IP3
PIP2 - phosphatidylinositol 4,5 bis phosphate - minor phospholipid in membrane
G protien
PIP2 - phosphatidylinositol 4,5 bis phosphate - minor phospholipid in membrane serves as the substrate for _
phosphatidyl identifies it as a phospholipid
phospholipase C
PIP2 cleaves phospholipase C into DAG and IP3
which product causes transient increase in [Ca++] increases binding of Ca++ to calmodulin, altering the structure of the Ca/Calmodulin complex
the complex is able to interact and activate numerous effector proteins
IP3
2 examples are
1. Calcium/calmodulin dependent protein kinase
- nitric oxide synthase
(NO-> guanylate cyclase -> GTP-> cGMP
PIP2 cleaves phospholipase C into DAG and IP3
which product actiavtes protein kinase c (PKC)
DAG
Ca++ dependent
most isoforms of PKC regulated bu DAG (DAG allows the enzyme to bind Ca tighter) therefore, the enzyme can function at lower Ca concentrations
how does the G protein receptor turn off
the trimeric G protein gets turned on, but it shuts itself off
the receptor gets turned off by a process called desensitization
phosphorylation by GRK(recruited by GbetaGgamma)
- binding by a Beta-arrestin
- formation of clathrin-coated pit
- endocytosis
the G protein coupled receptor after it has by desenitized/endocytosed it has one of two fates what are they
- recycling
- degradation
sometimes drugs are administered chronically, this can lead to loss of responsiveness to the drug and results that would seem paradoxical if one failed to consider desensitization
Signalign by receptor tyrosine kinases (RYK’s)
_ - critical
Doing the most important stuff inside cells - chemokines and cell signals and behavior
Binding of the ligand to the receptor leads to dimerization of the receptors - stuff does the most important things inside cells
Phospho tyrosine
accounts for 0.5% of the phosphorylated protein in cells
growth factors, differentiation factors, cytokines
RYK’s - receptor tyrosine kinases
- receptors either contain an intrinsic or extrinisic tyrosine kinase enzyme
- binding of ligand leads to _ of the receptor
- some receptors form homodimers, some receptors form heterodimers, and some receptors do both
- dimerzation leads to _ of receptors
- tyrosine phosphorylation of receptors leads to _ of signaling molecules
- the positioning of proteins near the _leads to different cascades of signaling
dimerization
most important things like chemokines, growth factors, cytokines
- leads to transphosphorylation of receptors
The receptors are phosphorylated - this is why they exist - important because leads to docking of signaling molecules
- phosphorylation leads to docking of signaling molecules
- proteins near the memrbane leads to different cascades
Ras
Grab 2 - docking site
Pattern of gene expression/regulation changed by tyrosine kinases
receptor tyrosine kinase example of signaling cascade
- binding of ligand(cytokine) leads to phosphorylation of receptor by _ kinase
- this leads to binding of _ protein (one of 6) to the phosphorylated receptor
- these leads to phosphorylation of STAT protein by Jak kinase
- this leads to dimerization of STAT protein
- this leads to translocation of STAT dimer to _ and transcriptional activation of panels of genes
- JAX kinase
- STAT protein
- to nucleus
_____________
STAT brings it to membrane so it can interact with tyrosine kinase
When 2 or more STAT do this - it has 2 parts
SH2 domain - docking
Dimerization affects interfureons
STAT-Jax RYK’s example
STAT monomers contain both an _ domain and a _ that can be phosphorylated
contain both a SH2 domain- docking
and a tyrosine that can be phosphorylated
To form an active protein to regulate gene expression
_ proteins mediate the profound biological responses to cytokines
STAT
receptor tyrosine kinases
receptors for steroid hormones (glucocorticoids, mineralcorticoids, testosterone, estrogens, progesterone) and other molecules such as Vitamin D, retinoic acid, thyroid hormone
nuclear hormone receptors
nuclear receptors are characterized as either class 1 or class 2
_ nuclear receptors exist as a complex with heat shock proteins in the absence of a ligand
ligand binding induces the compelx to fall apart, from a homodimer and bind to its specific DNA response element
once bound to its specific response element it binds coavtivaotrs to stimulate _
class 1
cofactors to stimulate transcription
Glucocortacoids - steroids - estrogens -
Intracellular receptors - HSP proteins form multi-protein complex
Cortisol comes in thru diffusion - bind and the shit falls a part
What exist on target genes - have a particular DNA sequence that is able to bind the receptor 2 molecules of glucocortico
Leads to activation complex
These receptors are themselves the thing
Bends then moves and becomes a part of the new DNA
Cofactors - lysine positive charge - dna negative charge - histone DNA interaction is basically electrostatic
If we want transcription to take place we have to loosen up the “bond” so we add HISTONE to lessen the negative charge -
in the nuclear receptors which class There is an activation complex being made in class _
class 1
class _ nuclear receptors activate target genes
ligand enters cell and binds to receptor
ligand receptor complex binds to specific DNA sequences on target gene
and expression of the target gene increases
they form 2
class 1
class _ nuclear receptors
binds to target DNA at its specific response element in the absence of ligand
binds corepressors in the absence of ligand and represses transcription
form homo and heterodimers
ligand binding produces a switch from binding corepressors to binding coactivators
class 2
In the absence of ligand - they don’t exist as dimer or two they sit right on DNA
Binding to target genes even in absence of ligand -
They bind corepressors
Takes actyl groups off the histones and making the electrostatic bond stronger
Inhibiting transcription of target genes
class 1 or 2 nuclear receptor ligands
thyroid hormone, retinoic acid, vitamin D
class 2
class 1 or 2 nuclear receptor ligands
glucocorticoids, progesterone, estrogens, androgens
class 1
which receptor
plasma membrane or organelle, signal by opening ion gates, drugs can affect synaptic transmission at different loci, liberation of Ca++ stores will have profound effect on cells
ligand activated ion channels
which receptor
Adenylate cyclase and the pleotrophic effects of PKA
phospholipase A2 and the liberation of arachidonic acid
phospholopase Cbeta and signaling by IP3 and DAG
receptor desensitization
G protein coupled receptors
which receptor
receptor dimerization, phosphorylation, docking of effectors
MAP kinase cascade-transcription factor activation, JAK-STAT pathway
signaling by tyrosine kinase receptors
which receptors
mechanism of action - class 1 and class 2 nuclear receptors
ligand activated nuclear receptors
