Lecture 9 Review Questions

survival, growth, differentiation, death

-acts by activating a transcription regulator; a hormone produced by adrenal glands, diffuses across plasma membrane binds to receptor protein in cytosol
-hormone receptor complex transported into nucleus through nuclear pores, cortisol binding activates receptor protein that binds regulatory sequences in DNA to activate or repress transcription

acetyl choline released by nerve, diffuses past smooth muscle and through basal lamina, reaches receptors on endothelial cells in blood vessel--cells make and release NO
-NO diffuses out of endothelial cells into smooth muscle cells to make muscle cells relax

-receptor protein on cell surface transduces extracellular signal into intracellular signal, initiatioes one or more signling pathways--relay signal to cell interior
-each pathway has intracellular signaling proteins that can function differently
-primary transduction-->relay-->transduce and amplify-->integrate-->distribute-->different effects

1.ion channel-coupled receptors
2.g-protein-coupled receptors
3. enzyme coupled receptors

1. nicotine: acetylcholine stimulates acetylcholine-activated ion-channel coupled receptors to constrict blood vessels and elevate blood pressure
2. morphine/heroin: endorphins stimulate G-protiein coupled opiate receptors providing analgesia (relief of pain) and euphoria

-3 protein subunits of g-protein: α,β and γ
-ligand binds, receptor changes, α loses affinity for GDP, exchange with GTP
-βγ subunit activated and can interact with target proteins in membrane
-α will hydrolize GTP back to GDP to stop signal (has intrinsic GTPase activity)

returns GTP to GDP, making protein go back to its original inactive conformation
-happens within seconds after G protein activation and it can be reactivated by another receptor
-just as important as what turns it on

ex: heartbeat controlled by acetylcholine--GPCR activates G protein (G_i), βγ complex is active sginaling component, binds to intracellular face of K⁺ channel in plasma membrane forcing the channel to stay in open conformation

1. increase in heart rate and force of contraction by adrenaline in heart tissue
2. glycogen breakdown by adrenaline in skeletal muscle
3. fat breakdown by adrenaline, ACTH, glucagon in fat tissue
4. corisol secretion by ACTH in adrenal gland

the hormone activates GPRC turns on G_s that activates adenylyl cyclase, raises production of cAMP, cAMP activates PKA that phosphorylates and activates phosphorylase kinase
-this kinase activates glycogen phosphorylase to break down glycogen--occurs rapidly because it doesnt involve gene transcription or protein synthesis

-rise in intracellular cAMP which activates PKA
-PKA moves into nucleus and phosphorylates specific transcription regulators, thse proteins stimulate transcription of set of target genes

-phospholipase C; some GPCRs activate PLC instead of adenylyl cyclase
- cleaves inositol phopholipid making IP3 and DAG (leads to two signaling pathways)

-IP3: water-soluble sugar phosphate that diffuses into cytosol, encounters ER where it binds and opens Ca++ channels, Ca++ stored in ER rushes into cytosol increasing the concentration, Ca++ then acts as signaling molecule
-DAG: helps recruit and activate protein kinase, PKC is activated by Ca++ then phosphorylates a set of intracellular proteins

NFAT-nuclear factor of activated T cells; 5 isoforms regulated by calcium signaling
-on activation there is an increase in intracellular calcium leading to the activation of calcineurin which dephosphorylates NFAT were it can translocate into the nucleus (get more info...)

-light is sensed by Rhodopsin (g-protein coupled light receptor), activates g protein Transducin, cyclic GMP phosphodiesterase molecules activated, GMP molecules hydrolized, cation channels close, membrane potential altered, nerve impulse sent to the brain
-signaling cascade adapts changing amplification in different light settings

-instead of coupling with g protein the cytoplasmic domain of the receptor acts as enzyme or associates with enzyme
-responses often slow and requrie many intracellular transduction steps that eventually lead to chagnes in gene expression
-can also mediate direct, rapid reconfigurations of cytoskeleton
-RTKs most common-receptor tyrosine kinases, most activate GTPase Ras

Ras activates MAP kinase signaling module; Ras activates three-kinase signaling module that relays the signal
-MAP kinase is phosphorylated and activated by MAP kinase kinase (MAPKK) and this protein itself is switched on my MAP kinase kinase kinase (MAPKKK); final activated protein is MAP kinase (which the module is named after)

-an extracellular survival signal like IGF activates RTK which recruits and activates PI3-kinase, which phosphorylates a membrane associated inositol phospholipid which attracts intracellular signaling proteins
-Akt is a protein kinase activated at membrane by posphorylation mediated by protein kinases 1 and 2, once activated Akt released from plasma membrane and posphorylates various downstream proteins on specific serines and threonines--stimulates cells to grown in size by activating tor

-mutant proteins can help determine exactly where intracellular signaling molecule binds, genetic analysis reveals the order in which singaling proteins act in a pathway (more info...)

-binding of prolactin to enzyme couple receptors causes assocaited tyrosin kinases (JAK1 and JAK2) to phosphorylate and activate each other
-activated JAKs phosphorylate receptor proteins, transcription regulators (STATs) in cytosol bind to pophotyrosines on receptor and JAKs phsphorylate and activate these proteins too
-activated STATs dissociate from recprot proteins, dimerize and migrate to the nucleus where the activate genes

-Notch?: direct signaling, delta binds, notch cleaved, notch tail goes to nucleus and transcribes notch responsive genes (notch receptor itself is a transcrition regulator)

-ethylene signaling pathway turns on genes by relieving inhibition, in absense of ethylene receptor directly activates a protein kinase that promotes dstruction of transcrition regulator that turns on ethylene response genes (gense stay turned off)
-in presene the receptor and kinase are both inactive and transcription regulator remains inact and stimulates transcription of genes