principles of cell signaling Flashcards
extracellular signals can travel long distances or short distances. give examples of local and long distance signals
short: contact dependent, paracrine
long: synaptic, endocrine
which part of signaling actually has the information and determines what the effects are?
receptors. the signal has little info, it just activates receptors. The same signaling molecule can have different effects on different target cells
what are the three major classes of cell surface receptor proteins?
Ion channel coupled receptors
G protein coupled receptors
enzyme coupled receptors
what does GAP do?
GAP drives proteins to the inactivated “off” state by increasing hydrolysis of GTP to GDP
what does GEF do?
GEF activates proteins “on” by promoting release of GDP and allowing GTP to bind.
does signaling always activate pathways with fast changes?
no. slow changes are also triggered when signaling leads to altered protein SYNTHESIS. when protein FUNCTION is altered, that is fast.
what are GPCRs? structure?
G protein coupled receptors. metabotropic plasma membrane receptors that couple to heterotrimeric G proteins. also known as Seven transmembrane receptors or Serpentine 7 receptors because they have 7 transmembrane alpha helices
what percent of all human genes encode GPCRs? what percent of drugs target GPCRs?
4% of human genes
40-50% of drugs
what are the subunits of heterotrimeric G proteins?
alpha subunit: molecular switch that changes shape depending on GTP or GDP bound. has lipid membrane anchor
beta subunit: forms dimer with gamma
gamma subunit: forms dimer with beta and has lipid membrane anchor
where does GTP/GDP bind on a heterotrimeric G protein?
in the AH domain within the alpha subunit
how does GDP binding impact affinity of G protein subunits for each other?
the alpha subunit has a high affinity for the beta/gamma dimer when GDP bound, it is inactive in this trimeric state
what causes the subunits to dissociate?
a GPCR is activated by a signaling molecule and is able to induce alpha to release GDP and bind GTP. alpha-GTP has decreased affinity for beta/gamma and it dissociates
GPCRs act as what to alpha subunit?
GEFs. the induce release of GDP and binding GTP, activating the G protein
what is the concentration of GTP vs GDP in the cytosol?
GTP: around 0.5 mM
GDP: around 10 times lower
This makes it so the G protein can easily bind GTP as soon as GDP is released
what interacts with downstream effector proteins?
either the activated alpha or beta/gamma subunits. they may activate or inhibit effector proteins
do alpha and beta/gamma always dissociate?
no. in some cells they remain bound but shift relative positions so interaction sites become available.
what is an effector antagonist?
a downstream effector protein that blocks signaling by physically blocking either alpha or beta/gamma. Ex. GRK2 binds beta/gamma
what are GRKs? what is their purpose? (Arrestin)
GPCR kinases that phosphorylate GPCRs and desensitize them. some proteins, like Arrestin, bind to phosphorylated GPCRs and block coupling to G proteins. Arrestin is an adaptor protein for clathrin and leads to endocytosis of the GPCR
four processes that block/reduce signaling through GPCRs
Inactivation: GPCRs are covalently modified to prevent them from acting as GEFs
Sequestration: GPCRs are endocytosed in to recycling Endosomes and are not exposed to agonist. may be recycled
Desensitization: same mech as inactivation
Down regulation: GPCRs are endocytosed and destroyed in lysosomes
what is yeast mating factor? what is the response to mating factor?
yeast mating factor is a secreted peptide that acts as an agonist for a GPCR on yeast PM. Haploid yeast that are ready to mate secrete mating factor peptide and other yeast respond by extending in that direction, called Shmooing
alpha subunits hydrolyze GTP slowly, what helps them accelerate this process?
GAPs accelerate GTP hydrolysis up to 1000 fold. for the alpha subunit specifically, Regulators of G-protein Signaling (RGS) is used as a GAP. PLCbeta1 acts as a downstream effector protein and functions as a GAP for alpha subunits (specifically Gaq/11). PLCB1 is negative feedback loop
there are many types of G protein alpha subunits in humans. name three
alpha S: activates adenylyl cyclase
alpha i/o: inhibits adenylyl cyclase
alpha q/11: activates phospholipase C
what does Cholera do to alpha subunit?
Cholera toxin can modify GalphaS to prevent GTP hydrolysis and result in constitutive signaling by alphaS until cell down refulates
what does Pertussis do to the alpha subunit?
Pertussis toxin can modify Galphai to block activation by GPCRs and causes whooping cough
