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Ch 16b Cell Signaling
Terms in this set (35)
Describe the components of signal transduction/intracellular signaling pathway.
extracellular signal (primary transduction)
1. Relay - Conformational change (signal is carried onward)
2. Transduce and amplify (make signal stronger)
3. Integrate (detect multiple signals)
4. Distribute (signal more than one effector)
Some intracellular signaling proteins act as _______ ________ causing them to toggle from an inactive to active state.
What are the two classes of molecular switches?
-Active/Inactive by phosphorylation - protein kinases (phosphatase takes off)
-GTP binding proteins - toggle b/w active and inactive depending on whether they have GTP or GDP bound.
What are the two main types of protein kinases?
-Most common serine/threonine kinases (attach phosphate to serines/threonines)
-tyrosine kinase (phosphate to tyrosines)
G proteins are intracellular signaling proteins that are named for their ability to to bind to _________ ________________.
guanosine triphosphate (GTP)
What are the two main types of GTP-binding proteins that participate in intracellular signaling pathways?
-Heterotrimeric G proteins
-Monomeric GTPases (RAS, superfamily of G proteins)
G proteins contain what kind of acitivity to hydrolyze GTP to GDP?
Monomeric GRP binding proteins are aided by which two regulatory proteins?
- GEFs, activate the switch proteins by promoting the exchange of GDP to GTP.
- GAPs, turn them off by promoting GTP hydrolysis
What are the 3 main classes of cell-surface receptors?
Ion channel-coupled receptor
Describe an Ion channel couple receptor
Change the permeability of the plasma membrane to selected ions, altering the membrane potential, produce an electrical current.
Simplest most direct way.
Important in nerve cells
Describe the G protein coupled receptor
Activate membrane bound, trimeric GTP binding proteins (G proteins), which then activate/inhibit an enzyme or an ion channel in the plasma membrane, initiating a intracellular signaling cascade.
G protein coupled receptors are _________ proteins with ______ membrane spanning regions.
Close to ______ distinct receptors have been identified in humans. Over _______ of them are expressed in the brain.
Describe how G proteins regulate ion channels of the heart pacemaker cells?
-Acetylcholine binds to receptor
-alpha (tethered to plasma membrane) separates from beta and gamma and exchanges GDP for GTP.
-beta and gamma (tethered to plasma membrane) moves to closed k+ channel.
-k+ channel opens to k+ can move out of the cell, cell becomes less positively charged.
-Heart rate slows (rapidly)
-Once beta and gamma removed, channel closes, GTP hydrolyzed, beta and gamma reattach to alpha.
What are the two most frequent target enzymes for G proteins and what do they produce?
adenylyl cyclase - cyclic AMP
phospholipase C - inositol triphosphate and diacylglycerol
Describe how G proteins (heterotrimeric) activate enzymes in skeletal muscle cells?
-alpha separates from beta/gamma, replaces GDP with GTP
-alpha bound to GTP activates adenylyl cyclase.
-sudden increase in synthesis of cAMP from ATP (can also activate phospholipase C, not discussed here)
-Protein Kinase A (PKA) binds with cAMP and acts as a secondary messenger
-Phosphorylase kinase get activated by ATP which activates glycogen phosphorylase by ATP
-Glycogen breakdown to glucose
-Fast response, will take seconds
How does cAMP signals also alter gene expression?
The active PKA is transported through the nuclear pore and phosphorylates
that turn ON or OFF target genes.
**will take hours
Describe how cAMP signal is turned off.
-Need to get rid of secondary messenger
-Cells use cAMP phosphodiesterase to convert cAMP into AMP
-AMP is reused in the cell and cAMP is only made again when new signal is received
The fight or flight response is mediated by multiple hormones acting through G proteins, describe adrenaline and cortisol.
-Adrenaline affects heart rate and metabolism; contracts mm cells below the surface of the skin causing perspiration and raised hairs
-Cortisol results in an increase in blood pressure and blood sugar levels, and suppression of the immune system
Describe how beta-blockers work.
Beta-blockers block the interaction between GPCR with adrenaline (epinephrine), makes the heart beats slower.
Describe how the cholera toxin protein alters the activity of G proteins
Bacterium multiplies int he human intestine (no clean water or sanitation), produces cholera toxin protein, enters cells that line intestine and modifies the alpha subunit, stimulates adenylyl cyclase.
**The modification prevents G protein from hydrolyzing its bound GTP and is stuck in the active state causing outflow of Cl- and water in the gut.
Describe enzyme coupled receptors
Transmembrane proteinsvwith ligand binding domains on outer surface of plasma membrane, but instead of associating with G proteins, the cytoplasmic domain acts as an enzyme itself (form an active dimer) or forms complex with another enzyme (dimerize and activate an associated enzyme)
Describe the activation of receptor tyrosine kinases
The binding of an extracellular molecule causes 2 receptors to come together in the plasma membrane to form a dimer.
-the pairing activates their kinase domains and each tail phosphorylates the other on specific tyrosines.
-Now can act as docking site, all possess a specialized interaction domain
An intracellular signaling protein that is activated by almost all RTKs is a small GTP binding protein called _____.
Ras, part of monomeric GTPase family
Describe the Mitogen activated protein kinase (MAPK) pathway
First Platelet derived growth factor (PDGFR) binds, dimerization and transphosphorylation take place. SH2 adapter attaches GEF (helps Ras exchange GDP for GTP), Ras is now activated with GTP
Activated Ras attached by lipid on cytosol side activates MAPKKK
MAPKKK phosphorylates MAPKK with ATP
MAPKK phosphorylates MAPK with ATP
**MAP kinase can phosphorylate various effector proteins including transcription regulators.
**May stimulate cell proliferation, promote cell survival, or induce cell differentiation
Describe GEFs and GAPs
GEFs= Guanine nucleotide exchange factor, helps Ras exchange GDP for GTP (turn on)
GAPs= GTPase, hydrolyzes GTP (turn off)
More than _____% of all human cancers are driven by mutation of Ras genes.
Disruption in ______ _______ signaling leads to disease. Ras is an _______ when mutated. Will not hydrolyze ______.
**mutation prevent Ras protein from being shut off, those signals to cancer cells to multiply, w/out the normal limits that control cell growth.
_____ activate the PI-3-kinase-AKT signaling pathway to promote ____ _______ and ________.
cell survival Akt
Describe the Phosphoinositide 3-kinase-Akt pathway
activated RTK Phos PI 3-kinase to activate
phosphorylates inositol phospholipid (PIP2) to form phosphorylated inositol phospholipid (PIP3)
Protein kinase 1 attaches to PIP3 to Phos Akt on one side and Protein kinase 2 on the other side
**Akt promotes survival by inactivating/Phos Bad to release active Bcl2, which inhibits apoptosis
AKT stimulates cells to grow in size by activating the Serine/Threonine (Ser/Thr) kinase _____.
**Activated Akt activates Tor which stimulates cell to grow both by enhancing protein synthesis and by inhibiting protein degradation.
An example of a receptor that does not have enzymatic activity.
1. Phos itself
2. Phos receptor (acts as docking site, recruits STAT)
3. Phos STAT
Too much inflammation, can be turned off this way
Which gas can diffuse across the membrane to the cell interior and directly regulate the activity of specific intracellular proteins?
nitric oxide (NO)
NO is synthesized from which amino acid?
arginine, NO diffuses from site of synthesis into neighboring cells.
Describe how NO affects smooth muscle cells .
NO signal causes smooth mm cells in the adjacent vessel wall to relax, allows dilation so blood flows more freely.
**Nitroglycerine is used to treat patients with angina to provide blood flow to the heart.
NO binds to and activates guanylyl cyclase which stimulates formation of cGMP. cGMP leads to the cell's ultimate response.
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