Chapter 16: Cell Communication71 cards

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1

Many of the intracellular signaling proteins behave as switches:

receipt of a signal causes them to toggle from an active state to an inactive state

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proteins that act as molecular switches fall mostly into one of two classes:

1- largest class: activated/inactivated by phosphorylation 2- GTP-binding proteins: switch between active and inactive depending on whether GTP or GDP are bound to them


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protein kinase

tacks a phosphate group onto the switch protein

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protein phosphatase

takes a phosphate off

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phosphorylation cascade

one protein kinase, activated by phosphorylation, phophorylates the next protein kinase in sequence, and so on, : amplification, distribution, and modulation

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two main types of intracellular protein kinases:

- serine/threonine kinases - tyrosines

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GTP-binding proteins

active/inact stated depends on whether GTP or GDP is bound


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GTP-binding proteins GDP bound

inactive - caused by GTPase: hydrolyzing


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cell-surface receptors fall into 3 main classes:

1- ion channel coupled receptors 2- GPCRs 3- enzyme coupled receptors

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ion channel coupled receptors

allow a flow of ions across the membrane , which changes the membrane potential and produces electrical current

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GPCRs

activate membrane bound , trimeric GTP-binding proteins (G proteins) which then activate either an enzyme or an ion channel in the plasma membrane, initiating a cascade

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enzyme coupled receptors

act as enzymes or associate with enzymes inside the cell

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the reason why a signal molecule can have two different effects in two types of muscle cells bc

there are different types of receptors in the different tissues thus generating different intracellular signals

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ion-channel coupled receptors are responsible for

the rapid transmission of signals across synapses in the nervous system

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when a NT binds to a ion channel coupled receptor, the receptor

alters its conformation so as to open or close an ion channel


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GPCRs from the

largest family of cell surface receptors - more than 700 in humans


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all GPCRs have a similar structure:

each is made of a single polypeptide chain that threads back and forth across the lipid bilayer seven times


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when an extracellular signal molecule binds to a GPCR, the receptor protein

undergoes a conformational change that activates a G protein on the underside of the plasma membrane

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G proteins are composed of

alpha beta and gamma subunits


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in the unstimulated state, the alpha subunit has

GDP bound to it and the G protein is idle

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when an extracellular ligand binds to a GPCR, the altered receptor

activates a G protein by causing the alpha subunit to decrease its affinity for GDP, which is then exchanged for GTP

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the activation of the alpha subunit of the G protein is thought to

break up the G protein subunits, such that alpha+GTP move away from beta+gamma = both complexes activated

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the amount of time that the alpha+GTP and beta+gamma complexes are activated is limited by

the behavior of the alpha subunit - intrinsic GTPase activity

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cholera is an example of a disease caused by a problem with a shut-off mechanism for a G protein switch:

toxin modifies the alpha subunit of a G protein in the intestine, remaining in active state indefinitely causing excessive outflow of Cl- and water into the gut

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whooping cough is an example of a disease caused by a problem with a shutoff mechanism for a G protein switch:

the alpha subunit is locked in its inactive GDP bound state = prolonged inappropriate signal - coughing

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the reason why when Ach binds to receptors in heart muscle cells it inhibits the cell's electrical excitability is because

when the subunits break apart, beta+gamma binds to a K+ channel ALLOWING IT TO FLOW OUT

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the two most frequent target enzymes for G proteins are

adenylyl cyclase--cAMP and phospholipase C--- inositol triphosphate and diacylglycerol

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in the case of adenylyl cyclase, the activated G-protein subunit switches

on the adenylyl cyclase synthesizing cAMP from ATP

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to terminate the signal when adenylyl cyclase is activated,

cAMP phosphodiesterase rapidly converts cAMP to AMP

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caffeine inhibits

phosphodiesterase blocking cAMP degradation

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cyclic AMP exerts most of its effects by

activating the enzyme cAMP dependent protein kinase

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what does PKA do?

when activated, catalyzes the phosphorylation of particular series or threonines on certain intracellular proteins, altering them

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once activated, phospholipase C propagates a signal by

cleaving a lipid molecule that is a component of the plasma membrane

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an inositol phospholipid is a phospholipid with

the sugar inositol attached to its head

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the signaling pathway that begins with the activation of phospholipase C is also called

inositol phospholipid pathway bc of the involvement of the inositol phospholipid

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the phospholipase C pathway works in the following way: (3)

1- the phospholipase C chops off the sugar-phosphate head off the inositol phospholipid, generating IP3 and DAG 2- IP3 (water soluble) diffuses into the cytosol 3- DAG remains in the plasma membrane

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when IP3 is cleaved in the phospholipase C pathway and released into the cytosol, what happens to it?

1-it encounters the ER where it binds and opens Ca++ channels 2-Ca++ rushes out signaling other proteins

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what does the DAG cleaved from the inositol phospholipid in the phospholipase C pathway do?

recruits and activates a protein kinase C - C bc it needs Ca++ to be activated

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Ca++ has a widespread role as a small intracellular messenger

egg to start development muscle contraction ***steep ECG at ER and PM

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calmodulin

Ca++ binds to this Ca++ responsive protein, and it undergoes a conformational change, wrapping round target proteins

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one of the positive advantaged of signaling cascades:

allows spectacular amplification and allows cells to adapt

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adaptation allows cells to

remain sensitive to changes of signal intensity over a wide range o background levels of stimulation

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enzyme coupled receptors are

transmembrane proteins that display their ligand binding domains on the outer surface of the plasma membrane but instead of associating with a G protein, the cytosolic domain of the receptor either acts as an enzyme or forms a complex with a protein that acts as an enzyme

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enzyme coupled receptor response are typically

slow (hours) eventually lead to changes in gene expression

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enzyme coupled receptors can mediate direct, rapid

reconfigurations of the cytoskeleton, controlling the way a cell changes its shape and moves

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the extracellular signals for architectural alterations (cell change in shape and movement) are

often proteins attached to the surfaces over which a cell is crawling

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enzyme coupled receptors have a major role in the development of diseases and disorders in

cell growth, proliferation, differentiation, survival, and migration

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largest class of enzyme coupled receptors is made up of those with

a cytoplasmic domain that functions as tyrosine protein kinase called receptor tyrosine kinases

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PKA, PKC, and CaM-kinases are all

serine/threonine kinases

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the only tyrosine kinases we discussed were

RTKs - receptor tyrosine kinases

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unlike the seven pass GPCRs, enzyme coupled receptors have

only one transmembrane segment = an alpha helix

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enzyme coupled receptors have a different strategy for transducing an extracellular signal,

bc it only has one membrane spanning alpha helix. so - binding of the signal molecule causes: 1-two receptor molecules come together to form a dimer 2-activating kinase fxn 3- phosphorylate each other 4-triggers the assembly of elaborate intra. sign. complex

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to help terminate the response in the RTK cascade,

tyrosine phosphorylations are reversed by protein tyrosine phophatases


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Ras

small GTP-binding protein that is bound by a lipid tail to the cytoplasmic face of the PM

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the Ras protein is a member of

a large family of small GTP-binding proteins (monomeric GTPases)

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Ras resembles the

alpha subunit of a G protein and functions in much the same way: GTP bound GDP bound

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MAP-kinase signaling module

three-kinase protein module that carries a signal from the PM to the nucleus


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cytokines

bind to receptors that can activate transcription regulators that are held in a latent state near PM BUT once activated head straight for the nucleus


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in Drosphila, what intrinsic properties does a notch receptor possess ?

a transcription regulator: - activated by the binding of delta (attached to a neighboring cell) -notch receptor cleaved -releases cytosolic tail of the receptor - tail heads to nucleus -activates genes

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the notch receptor- delta signal protein complex utilize

the simplest and most direct way known to transmit a signal from a cell-surface receptor to the nucleus