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WVSOM - Molecular-2

Transport Proteins, Receptor Biology, Signal Transduction

QuestionAnswer
Receptor characteristics Specificity (only recognize & bind one/few ligands), high binding affinity for ligand, saturable binding, reversible binding, tissue specific distribution, biological response
Characteristics of hydrophilic ligands Cannot transverse membranes (bind extracellular domain of transmembrane receptor), transported free in blood plasma, easily stored in gland cell vesicles (preformed stock rapidly secreted as needed), rapid responses, short 1/2-life, rapidly cleared
Characteristics of hydrophobic ligands Pass membranes to bind intracellular receptors, require binding proteins to be transported in blood, difficult to store in cells (synthesized as needed), slow responses, long 1/2-lives (hours to days)
Receptor regulation Receptor number, affinity for ligand, affinity for intracellular targets, cellular localization, membrane fluidity
Receptor A cellular factor that recognizes and binds a specific ligand to induce a response
Ligand A molecule bound by another molecule such as a receptor
Isoreceptor Different receptors bound and activated by the same ligand, often inducing distinct responses in different cells
Paracrine For an intercellular signaling molecule to diffuse over a short distance, usually through interstitial spaces, to induce a response
Endocrine For an intercellular signaling molecule to diffuse through the blood
Intercellular signaling molecule A non-nutrient ligand secreted by one cell to induce a response in another cell (ex: hormone, growth factor, cytokine)
Hormone An intercellular signaling molecule that controls metabolism or physiology
Growth factor An intercellular signaling molecule that controls cell cycle progression, cellular differentiation, or morphogenesis during development
Cytokine A growth factor involved with hematopoiesis (immune system)
Hydrophobic ligands Steroids (cholesterol derivatives) and FAT derivatives (prostaglandins, retinoic acid)
Hydrophilic ligands AA derivatives (catecholamine-tyrosine, histamine-histidine, serotonin-tryptophan), peptides and proteins (insulin, glucagon, FSH, TGF-beta, etc.), nucleotides (ADP for platelets, cAMP for slime molds), NO CARBS!
Kinetics Receptor characteristics (binding rate, affinity, saturability, reversibility) quantified with formulae (Scatchard analysis) derived from Michaelis-Menten equation from enzyme kinetics
Nuclear receptors "Steroid receptors", hydrophobic ligands, cyto-nucleoplasmic (NOT transmembrane), zinc-finger TF; constitute gene family (similar sequences, similar structures, same basic mechanism)
Nuclear receptor sub-families Glucocorticoid family (glucocorticoid & testosterone receptors), estrogen receptor, non-steroid family (thryoid hormone, retinoic acid); members of subfamilies related to each other than to members of other 2 families
Types of intercellular signaling molecules Nuclear receptors and transmembrane receptors
Transmembrane receptors Binding for hydrophilic ligands; 3 domains: ligand binding domain (extracellular side), hydrophobic transmembrane domain (spans membrane), signal transduction domain (cytoplasmic side)
Extracellular ligand binding domain Extracellular side of membrane, domain binds ligand or may be bound by ligand, ligands with binding activities are usually proteinaceous hormones or growth factors, receptor binding domains recognized by ligands = short oligosaccharides
Transmembrane domain Able to propagate signal from ligand on extracellular side of membrane to cytoplasm; receptor must transverse lipid bilayer
Signal transduction domain Receptor must be able to interact with signal transduction factors on cytoplasmic side; usually enzymatic reaction
Transport protein receptors Receptors that act as transport molecules; ligand binding opens passageways, allows specific factors to pass through; passageway considered signal transduction domain (i.e. ligand-gated channels)
Ligand-gated channel Neural transmitter = ligand; induce channel opening (closing), allowing specific ions to pass through membrane; action potential propagated from one cell to another
Passive diffusion Spontaneous movement of molecules without expenditure of energy, down concentration gradient (high-low concentration), move with electric potential (to area with opposite charge)
Facilitated diffusion Passive diffusion through specific transmembrane proteins (channels or transporters)
Facilitated diffusion v. passive diffusion Facilitated diffusion = specific (only certain molecules or ions to pass), faster, saturable (limited number of channels or transporters)
Vmax Maximal diffusion rate when all transport proteins are occupied
Active transport Forced movement across a membrane, driven by expenditure of energy (usually ATP hydrolysis), against concentration gradient / electric potential
Transport proteins Facilitated diffusion or active transport; only allow certain factors to pass; 1. transmembrane domain, 2. polar head domain (interact with membrane), 3. hydrophobic face (interact with lipid bilayer), 4. hydrophilic passageway
Types of transport proteins Channels, transporters, ATPase pumps
Channels Mediate facilitated diffusion (single file flow of factors through protein), selective (only allow one type of factor to pass), gated (close in response to stimuli)
Transporter Pass one factor (or set of factors) at a time by conformational change of protein
ATPase pumps Mediate active transport by directly hydrolyzing ATP; four types (P class, F class, V class, ABC class)
Types of transporters (CAREFUL: NOT transport proteins) Uniporters, symporters, antiporters
Uniporter Transport one factor across membrane
Symporter Simultaneously transport two factors in same direction
Antiporter Simultaneously transport factors in opposite directions; used to drive compounds down [ ] gradient (or electric potential) to provide energy to drive another compound against gradient; energy stored in membrane by separate ATPase that establish gradient
P class ATPase Ion pumps (Na+/K+ ATPase); energy from ATP hydrolysis (phosphorylates residue on subunit of pump); induces conformational shift allowing factor to pass against gradient
F class ATPase Proton pumps (mitochondria); produce ATP; H+ through pumps (high to low []); proton current drives ADP phosphorylation (i.e. reverse ATPase)
V class ATPase Proton pumps (lysosomes, osteoclasts); lower pH; produce acidic lumens; separate transport proteins required to import neg. charge or export positive charge (required for lowering pH)
ABC class pumps ATP binding cassette; largest and most diverse class of ATPase pumps; transport wide range of factors; examples = multidrug-resistance protein (MDR-1) and Cystic Fibrosis transmembrane conductance regulator (CFTR)
ABC ATPase: Multidrug-resistance protein (MDR-1) Excretes hydrophobic compounds from tissues (ex: liver); toxins hydrophobic; MDR-1 detoxifies cells; drugs hydrophobic (also excreted); identified in tumor & tissue cultures (acq. resist. to hydrophobic chemo; mutations caused cell to overexpress pump)
ABC ATPase: CFTR Functions as channel; ATP hydrolysis req. to open channel (once open, ions flow passively); regulatory domain (phosphorylated by cAMP signaling to open channel)
CFTR in lung CFTR open=Cl- to flow into mucus lining airways; phosphorylated=Na+ channel repressor (few Na+ diffusing into epithelial cells); effect=raise [NaCl] in mucus, raise osmotic pressure, draw H2O into mucus, raise mucus fluidity, ciliary beating clears mucus
Cysic fibrosis No functional CFTR; [Na+], [Cl-] not raised in mucus, collects in airways, too viscous for cilia to move; airway obstructions; growth of Pseudomonas aeruginosa (deteriorates lung tissue)
Cystic fibrosis secondary symptoms CFTR channel locations = lung, pancreas, sweat glands, liver, large intestine, testes; secondary symptoms = salty sweat, male sterility, pancreatic hypoglycemia; multiple symptoms from single gene = plieotropy
Mechanism for transporters and P class ATPases Two binding sites for translocated factors; positioned on each end of transmembrane passage; one = high affinity, one = low affinity; two conformational states (E1, E2)
E1 and E2 E1=Resting conformation; high affinity (E1) binding site open, low affinity (E2) closed; E1 site binds factor to be transported; causes conformational shift in E2 (E1 closes, E2 opens); factor translocated through passageway to low affinity (E2) site
Symporter transporter mechanism Multiple binding sites (low affinity on one side, high affinity on the other)
Antiporter transporter mechanism High and low affinity sites on opposite side of the membrane
P class ATPase transporter mechanism Similar to high and low affinity binding (E1, E2); additional ATPase domain for binding & hydrolyzing ATP; phosphate (from ATP) forces transport protein to shift from E1 to E2; factor translocated to low affinity site
Higher concentrations on exoplasmic side of membranes Na+, Ca2+, Cl-
Higher concentrations in cytoplasm K+, HCO3
Electric potential difference across membrane 30-70 mV (~200,000 V/cm)
Term for membrane in reference to electric potential Capacitor (thin barrier separating opposite charges)
Na+/K+ ATPase Establish electric potentials across membranes (also Na, K gradients); pump exports 3 Na+, imports 2 K+ for every ATP hydrolyzed; exoplasmic greater (+) than cytoplasmic (-); potential amplified due to lots of K+ channels (diffuse out of cell)
Na+/K+ ATPase equilibrium Established between diffusion of K+ out of cell and electrical force driving it in
Function of Na+/K+ ATPase Store energy across membrane for other transport proteins to utilize to drive factors against their concentration gradients
Erythrocyte energy expenditure to maintain electric potential/concentration gradient 50%
Kidney cell energy expenditure to maintain electric potential/concentration gradient 25%
Signal transduction pathways Regulatory pathways that transduce signals into cells; signals begin w/ intercellular signaling molecules (hormones/growth factors), interact w/ transmembrane receptors to transduce signal thru plasma membrane to intracellular effectors & 2nd messengers
Effectors Components of signal transduction pathways; signal propagated from upstream to downstream effectors
2nd messenger Effectors that change concentration (increase or decrease) in response to ligand-receptor binding (i.e. cAMP, DAG, IP3, Ca2+)
Signal transduction pathways TGF-beta, Ras-MAPK, cAMP, phosphoinositide
Properties that explain diversity of transduction responses 1. different versions of each pathway (homologous factors for each step), 2. response to pathway depends on cellular context (different downstream targets), 3. crosstalk between pathways (regulate each other)
Receptor: Tyrosine kinase Activates Ras-MAPK > phosphoinositide
Receptor: G protein coupled Activates cAMP = phosphoinositide
Receptor: G protein coupled > tyrosine kinase Activates phosphoinositide
TGF-beta signaling Family of proteinaceous intercellular signaling molecules controlling numerous developmental events from embryo to adult (i.e. mesoderm induction, tissue polarity, cellular proliferation, bone morphogenesis, immunosuppression)
Serine/threonine kinase receptors Receptors that bind TGF-beta homologs; heterotetrameric (type II, I); II phosphorylates serine/threonine residues on I, activates kinase activity; I phosphorylates specific serine residue of effector = Smads
Smads (Sma and mothers against decapentaplegic) Effector molecules for TGF-beta signaling (two forms - receptor regulated Smads, coSmads)
Receptor regulated Smads Specific to particular TGF-beta like pathways; phosphorylated by activated receptors; phosphorylation induces them to associate with coSmads
coSmads Common factors for all TGF-beta pathways; different receptor regulated Smads bind same coSmad (Smad4 in vertebrates); not phosphorylated; bind with receptor regulated Smads that have been phosphorylated
Heteromeric Smad complex Receptor regulated Smads + coSmads: translocate to nucleus, function as transcription factors, control gene expression by binding recognition sequences to activate / inhibit transcription of specific genes
Pathway conservation Homologous versions of same transduction pathways used to induce diff. responses; entire pathways duplicated & diverged to fulfull distinct roles; common characteristic of all; helps account for complex responses controlled by few pathways
Ras-MAPK Signaling Pathway activated by tyrosine kinases; controls blood glucose levels, metabolism, cell cycle progression, differentiation, apoptosis (i.e. insulin - activates hepatic RasMAPK that dephosphorylates glycogen synthase to induce glycogen synthesis)
Tyrosine kinase receptors Form dimers; subunits associate in response to ligand binding; one class where subunits covalently linked
Transautophosphorylation Ligand binding & dimerization induces receptors to phosphorylate themselves (auto); each subunit phoshorylates other member of dimer (trans); induces complex of 3 effectors (adaptor, GEF, Ras) to form around signal transduction domain
Ras-MAPK: Adaptor protein (ex: GRB2) First factor recruited into complex around phosphorylated tyrosine kinase receptor
Ras-MAPK: GEF Guanine nucleotide exchange factor (ex: son of sevenless-SOS); factor recruits final component of complex, Ras; functions to dislodge GDP bound to Ras; Ras auto. refills binding site w/ guanine; usually grabs GTP b/c it's much more conc. in cell than GDP
Ras-MAPK: Ras Activated by GTP binding, allowing it to serve as cofactor for downstream kinases, such as Raf
Ras-MAPK: GAP (GTPase activating protein) Deactivates Ras; serves as cofactor for intrinsic GTPase activity (Ras); induced-Ras dephosphorylates GTP, convert to GDP; prevents Ras from activ. downstream kinases; always present=always inactiv. Ras; TK receptor repeatedly bound to perpetuate response
Ras-MAPK: MAP (mitogen-activated protein) kinase cascade Downstream leg of Ras-MAPK; Ras-GTP activates Raf; phosphorylates & activates MEK (MAP & ERK kinase); MEK phosphorylates & activates MAP kinase; phosphorylates numerous proteins (enzymes, transcription factors, microtubule associated proteins)
Activation cascade Every kinase molecule activates goes on to phosphorylate 100's of downstream molecules, so that signal is amplified exponentially from step to step; robusst responses induced by minute signals
cAMP signaling Pathways controls many processes; ex: glucagon in liver, adrenaline w/ liver & adipose; activate glycogenolysis (phosphorylates glycogen phosphorylase), inhibit glycogen synthesis ( phosphorylates glycogen synthase)
G protein coupled receptors Activates cAMP, phosphoinositides; transmembrane=7 alpha-helices, loops in cytoplasm & exoplasm; ligand binding=helix 7 (ligand specificity),3,5,6 (bind ligand); signal transduction=C terminus+loop btw helix 5,6 (regions interact with G protein effectors)
G proteins 1st effectors of cAMP; 3 forms (G-alpha, G-beta, G-gamma); assoc. into trimeric complex, bound by G protein coupled receptors; ligand binding induces conformation change (receptor); receptor exchanges GDP (at G-alpha) for GTP; G-alpha dissoc. from trimer
G-alpha-GTP binds what after dissociation from trimer Adenylate cyclase
Gs-alpha Activate adenylate cyclase; controlled by separate ligands and receptors
Gi-alpha Inhibit adenylate cyclase; controlled by separate ligands and receptors
G-beta,gamma controlling activity Some brain adenylate cyclases, heart K+ channels, yeast mating type
Adenylate cyclase Converts ATP to cAMP, forming internal phosphodiester bond between 5` phosphate and 3` -OH; done so when bound by Gs-alpha
cAMP Serves as 2nd messenger, activating protein kinase A
cAMP phosphodiesterase Deactivates cAMP signal, converts it back to AMP
Protein kinase A Enzyme activated by cAMP, inactive form exists as tetramer (2 regulatory - R; 2 catalytic - C) subunits; cAMP bind R, inducing conformational shift (releases & activates C); C phosphorylate serine & threonine of specific proteins
IP3 (inosital triphosphate) Six carbon ring with three phosphates
DAG (diacylglycerol) 2 fatty acyl side chains esterified to glycerol; 1 FA saturated, other is arachidonic acid (precursor for prostaglandins, aspirin prevents inflammation by blocking pathway converting arachidonic acid to prostaglandins)
PIP2 (phosphatidylinositol biphosphate) Substrate of PLC; products = IP3, DAG; PIP2 & DAG are integral membrane factors b/c of fatty acyl side chains; IPs released into cytosol
PLC (phospholipase C) Enzyme is 1st unique effector in phosphoinositide pathway; activated by Gq-alpha-GTP (PLC-gamma = activated by tyrosine kinase receptors) to catalyze cleavage of PIP2 into IP3 & DAG
Phosphoinositide signaling Use G protein coupled receptors with G protein homologs = Gq (Gq-alpha, Gq-beta, Gq-gamma); control metabolism, cell cycle progession, hormonal secretion, transport protein activity, cardiac & neuronal electric signal propagation, mental health
Phosphoinositide pathway: PLC-gamma Activated by tyrosine kinase receptor
Pertussis toxin Prevents release of GDP from Gq-alpha, blocking PLC activation; prevents GDP release from Gi-alpha protein, preventing adenylate cyclase inhibition; leads to whooping cough
Ca2+ IP3 binds & opens Ca2+ gated channels (vesicles, ER); ion in cytosol = 2nd messenger; secreted in waves, believed to concentrate signal at peaks; serves as cofactor (controls activity of transport proteins, enzymes); induces muscle contraction
Ca2+ in crosstalk Stimulates phosphodiesterase (reduces duration of cAMP signaling)
Protein kinase C (PKC) Target of Ca2+; central enzyme; Ca2+ causes PKC to assoc. w/ plasma membrane; binds DAG (functions as cofactor - activating kinase activity); PKC phosphorylates various proteins (TF, enzymes); signal inactivated by rejoining IP3 & DAG = PIP2
Lithium Treats manic depressant patients; dampens mood swings; blocks phosphoinositide signaling by inhibiting one enzyme involved w/ rejoining IP3 & DAG; proposed to inhibit Gq
In cAMP signaling, who exchanges GDP for GTP? Receptors; G proteins do not have GEF-like factors that can exchange GDP for GTP
Cholera toxin Inhibits GAP domain G-alpha, prevents deactivation of signal, leads to massive diarrhea and death due to dehydration
What inactivates the G-alpha domain in cAMP signaling? Ras domain of G-alpha binds GTP, GAP domain induces hydrolysis of GTP to GDP, inactivates signal
G-alpha domain is similar to ... Ras; AA sequence is similar; also, GAP is similar; structure of G-alpha similar to Ras and GAP when they are bound to each other
Created by: JaneO on 2011-09-29



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