Week 2 Flashcards
Endocrine chemical messenger cells:
secrete hormone into the blood
specific target cells that can be very far away
usually high concentrations to react all over body (insulin, glucagon, cortisol)
Paracrine chemical messenger cells:
Actions performed on nearby cells
Only need low amounts of secretions to only act locally
Location of cells plays a role in specificity of response
Autocrine chemical messenger cells:
Act on the cell from which it is secreted or on nearby cells that are of the same type
Most autocrine cells are also paracrine cells
Hydrophobic chemical messengers are specific for _______ _______
Intracellular receptors (Ex: Steroid hormones - cortisol) - also called Lipophilic hormones
For intracellular receptors and hydrophobic messengers like cortisol, are they fast or slow to change cellular phenotype after eliciting a transcriptional response?
Slow
______ chemical messengers are specific for plasma membrane (cell surface) receptors.
Hydrophilic
What are the examples of the Cell surface membrane receptors?
Serine/threonine kinases (heterodimirical)
Tyrosine kinases (insulin)
Jak-STAT signaling
G-protein coupled receptors
How do cell surface membrane receptors change enzyme activity ? direct or indirect? what type of interactions? Fast or slow to change phenotype?
Direct
Protein-protein interactions
Fast to change phenotype
What does cortisol need to attach when traveling in bloodstream due to it being hydrophobic?
Attach to serum albumin (plasma protein) and steroid hormone binding globulin
Where is cortisol released from?
Adrenal Cortex and diffuses into bloodstream
What does Cortisol bind to?
Cortisol receptors (intracellular) in the cytosol after diffusion through plasma membrane
What are the 3 domains of the Cortisol receptors?
- Transactivation Domain
- DNA binding domain
- Ligand binding domain
What does the Ligand binding domain on Cortisol receptors do?
Causes conformation change in receptor
- Dimerization of receptors
- Exposes a nuclear translocation signal- allows hormone receptor to cross the nuclear membrane into nucleus
What does the Hormone receptor complex for Cortisol do once in the nucleus?
Acts as transcription factor
-Binds to portion of DNA called the hormone response element or GRE (glucocorticoid response element)
What is the name or the section that the hormone receptor complex for cortisol binds to once in the nucleus?
Glucocorticoid response element (GRE)
-or called hormone response element
What happens after the Glucocorticoid response element (GRE) is bout to by the cortisol receptor hormone complex once inside nucleus?
Induction (increase) or Repression (decrease) in gene transcription depending on the location of the GRE that is bound on DNA
How is the signal that the cortisol receptor induces terminated? where in the chain of events?
Cortisol concentration is lowered by the liver destroying cortisol (degrading) so that less signaling occurs
Where are Tyrosine Kinase receptors (insulin signaling)?
TK receptors are in the cell membrane (transmembrane)
-Function as dimmers
What happens after the insulin hormone binds to the receptor?
Autophosphorylation occurs on inner side of receptor
IRS (insulin receptor substrate) protein is then bound to receptor and forms a phosphorylated tyrosyl residue (tyrosine) at multiple sites
What happens during the tyrosine kinase insulin pathway after the tyrosyl residue is phosphorylated on the IRS proteins?
Multiple different proteins can bind to different phosphorylated tyrosyl residues
What different proteins can bind to the phosphorylated tyrosyl residue on the IRS protein that is bound on the intermembrane side of the insulin hormone receptor?
PI-3 kinase (Phosphoinostitol 3 Kinase)
PLC (Phosophlipase C)
Grb2
(all have SH2 domain that binds to different sites on phosphate group of IRS protein)
What does the Grb2 bind in the specific Insulin pathway (Tyrosine Kinase pathway example)?
Activated Grb2 binds to GAP1 (or a SOS-GEF) which is connected to a PIP in the membrane
What happens to the SOS-Ras complex after is has a conformation change in the general Tyrosine Kinase pathway and GDP was exchanged for GTP?
Ras-GTP binds to Raf to activate it
What is the purpose of activating Raf in the general Tyrosine kinase pathway by the Ras-GTP complex?
Activated Raf is the first step in a MAP-kinase cascade that can lead to a change in gene transcription
What does PIP stand for in the insulin tyrosine-kinase signaling pathway?
Phosophtidylinositol signaling
What does the Pl-3 kinase do to the PIP in the membrane during the insulin tyrosine kinase pathway?
Recognizes PI 4,5-bisP and phosphorylates it into PI 3,4,5,-trisP (just adds one phosphate group)
What happens after the PI 4,5-bisP is turned into PI 3,4,5-trisP in the insulin tyrosine-kinase pathway?
Phosphoinostitol Dependent Kinase 1 (PDK 1)
and
Protein Kinase B (PK B)
both are attracted to side due to their pleckstrin homology domains and both bind
What is the similarity that PDK 1 and PK B share that attracts both of them to bind PI 3,4,5,-trisP in the insulin tyrosine kinase pathway?
both have Pleckstrin Homology domains for binding
What happens after PDK1 and PKB are bound to PI 3,4,5, trisP in the insulin tyrosine kinase pathway?
PKB (protein Kinase B) is phosphorylated and activated by PDK 1 (Phosphoinostitol Dependent Kinase 1)
PKB is released in active form as second messenger to trigger MAP Kinase signaling pathway downstream (analogous to Raf protein in general Tyrosine-kinase pathway)
In the general Tyrosine kinase pathway, what does Grb2 have bind to it and activate ?
Once Grb2 is bound on SH2 side, conformation change occurs on SH3 domain (opposite side) and attracts a protein SOS (Guanine exchange factor or GEF)
What does SOS or GEF (Guanine exchange factor) do in the general tyrosine kinase pathway?
binds with Ras which is bound on the inner leaflet of the cellular membrane
In the general Tyrosine-kinase pathway, what happens after the Ras is bound by GEF?
the Ras is holding GDP and it is exchanged for GTP which then attracts Raf to bind to it to activate Raf
What is the purpose of activation of the Raf that binds to Ras holding GTP?
MAP kinase signaling pathway is activated to elicit transcription response/cellular response induced by the original signaling molecule outside the cell
What does MAP kinase stand for?
Mitogen-activated protein kinase
-are specific to serine, threonine, and tyrosine
What are the sites by the Ligand binding domain on the steroid hormone receptor (Glucocorticoid receptor)?
Dimerization sites
Inhibitor binding sites
NLS
What is another name for the Glucocorticoid receptor?
Steroid hormone receptor (intracellular receptor) for cortisol
What is the example of an Intracellular receptor ?
Glucocorticoid receptor (steroid hormones)
What are the three main domains on the Glucocorticoid receptor (intracellular)?
Transactivation Domain (TAD) DNA- binding domain (DBD) Ligand binding Domain (LBD)
What are the 3 extra sites on the Glucocorticoid receptor that are near the Ligand binding domain ?
Dimerization sites (Dimer-Dimer formation)
Inhibitor-binding sites
Nuclear Localization signal (targets it to nucleus)
In the absence of Ligand in the cytosol, what are the two proteins that are bound to eachother keeping the Glucocorticoid Receptor inactive (GR)?
Heat-shock protein is bound to the GR
What happens when cortisol is present in the cytosol to the heat-shock protein and GR?
heat-shock protein releases from GR
Cortisol will bind as substrate to GR, activating GR
What happens when GR is activated by Cortisol binding?
Conformational change (Dimer-Dimer formation) and 3 sites are exposed now: Transactivation domain (TAD) DNA-binding domain (DBD) Nuclear localization signal (NLS)
Where does the GR that has been activated bind to once it has entered the Nuclear pore and the nucleus?
GRE = Glucocorticoid response element
-specific site on DNA upstream from transcription site
What does the GRE in the nucleus do once it is activated by Glucocorticoid receptor ?
Can increase induce or repress gene transcription based on location of GRE that is bound:
Recruit Co-Acivators that are associated with activating:
Basal transcription complex - increases gene transcription
HORMONE RECEPTOR COMPLEX is a Transcription factor
Glucocorticoid response element (GRE) in nucleus on DNA is upstream of many genes for transcription, so in the presence of ________ there are changes in transcription of many different genes.
Cortisol
What other substrates act similarly to the Cortisol pathway for intracellular receptors that are transported into the nucleus?
Vitamin D
Retinoic Acid
Cortisol
What is different in the Serine-Threonine Kinase receptors from the Tyrosine kinase receptors?
Receptors usually form heterodimers instead of homodimers
Type II receptor will autophosphorylate the type 1 receptor upon ligand binding
What happens in Serine-Threonine Kinase pathway (in TGF-Beta example) after the Type 1 receptor is phosphorylated by the Type II receptor to be activated?
Serine phosphorylated section of Type 1 receptor recruits:
R-Smad proteins
What happens after R-Smad proteins are bound to the phosphorylated Serine on the Type 1 receptor for the TGF-Beta receptor?
R-smad phosphorylates itself on several Serine sites
What happens after R-smad phosphorylates itself on its own Serine sites?
R-smad is released and then binds with Co-Smad and makes a complex that migrates to nucleus to impact transcription
What is the basic structure of a G-Protein receptor complex?
- Heptahelical receptors (7 alpha helixes) on external membrane with 7 transmembrane domains
- Heterotrimeric G-protein on intracellular membrane
- G-protein itself has an Alpha, Beta, Gamma section that spilts to activate separate pathways
What 3 pathway signaling cascades with G-Protein potentially activate?
cAMP DAG IP3 (all second messengers) -leads to cellular response
What happens after a ligand binds to the heptahelical receptor connected to G-protein?
G-alpha-S subunit of G-protein is holding GDP and exchanges it for GTP (site conformational change to face more cytosol where [GTP] is higher so it will exchange) to activate the subunit and dissociate it from Beta and Gamma units
what happens after G-alpha-S subunit of G-protein after it dissociates from the Beta and Gamma units and the membrane (activated by exchanging GDP to GTP) ?
G-alpha-S binds and activates Adenylyl cyclase protein in membrane and keeps it active until EXHANGES own GTP back for GDP+inorganic phosphate group through hydrolysis and unbinds
What happens when the Adenylyl (Adenylate) cyclase is activated by G-alpha-S ?
Adenylyl cyclase turns ATP into cAMP (second messenger)
What happens to the phosphate groups when ATP is converted by Adenylyl cyclase to cAMP?
chain of 3 phosphates taken away and only one phosphate group is left that has 1 Oxygen on Carbon3 and one on Carbon 5
(aka 3,5-cyclic AMP)
What is the other name for cAMP?
3,5,-cyclic AMP
What regulates cAMP? where is it located?
cAMP phosphodiesterase
Found in cell membrane - intracellular side
What type of regulation and what does it do:
cAMP phosphodiesterase ?
Negative regulation- degrades the cAMP back to 5-AMP from cAMP so that the phosphate group is attached like it was on ATP (but just one phosphate group hence the “M”)
What does ATP stand for ?
Adenosine triphosphate
What is the example of the G-Protein receptor complex pathway?
Glucagon receptor
What happens in the Glucagon receptor pathway (G-protein example) after cAMP is produced by Adenylyl cyclase ?
cAMP is second messenger and binds Protein Kinase A in regulatory subunit-cAMP and activates PKA
What does an activated Protein Kinase A in the glucagon receptor pathway do (G-protein example)?
Leads to phosphorylation of many proteins in metabolism in cytosol
- Glycogen synthase is inactivated by phosphorylation (ATP to ADP used)
- Phosphorylase kinase is activated by phosphorylation (ATP to ADP used)
What happens in Glucagon pathway after the Protein Kinase A activates Phosphorylase Kinase by phosphorylating it?
- Phosphorylase kinase will phosphorylate the inactive Phosphorylase-B into active form Phosphorylase-A
- Phosphorylase A used to degrogate Glycogen in liver (break down)
How do you regulate cellular messaging at the secondary messenger level?
- Diffusion degradation
- Desensitization downregulation (excessive messengers)
- Phosphodiesterases can degrogate cAMP or second messengers
How do you regulate the G-Protein at the G-aplpha-S subunit level?
Using GTPases that reduce GTP back to GDP preventing the G-Alpha-S subunit from activating
What are Jak-STAT proteins also referred to as?
Tyrosine Kinase ASSOCIATED receptors
What is different from Jak-STAT receptor proteins and normal Tyrosine kinase receptors like in insulin pathway?
Jak-STAT proteins do not have intrinsic Tyrosine activity, but bind a Tyrosine Kinase (Jak type) that are the ones phosphorylated
What happens in the first step of Jak-STAT proteins?
Cytokines bind to receptors, both receptors dimerize and bind Jak (Janus Kinase)
What does Jak in Jak-STAT stand for ?
Janus Kinase
What happens after Jak binds to the transmembrane receptors?
Autophosphorylation of the Jak and then of the Receptor ends too
What happens after the Jak (Janus Kinase) and their receptors they are bound to phosphorylate?
Recruits STAT family of proteins that are phosphorylated (gene specific transcription factors = more direct than tyrosine kinase normal pathway) - will directly translocate to nucleus and impact transcription
-STATS dissociate from receptor, dimerize, then translocate into nucleus
What does Phosphatidylinositol 3’4’5’-tris-phosphate (PI-3,4,5, trisP) serve as in the cell?
plasma membrane docking site for signal transduction proteins with Pleckstrin homology (localizes the bound proteins to cell membrane)
What two proteins have Pleckstrin homology domains?
PKD1 (phosphinostitol kinase dependent 1)
PKB (Protein Kinase B)
Some downstream signaling of GPCRs involve activation of _________. A G-protein designated ____ activates one form of it.
Phospholipase C
Gq (G-protein)
When a particular GPCR (receptor) is activated, GTP exchanges for GDP, then Gqa-GTP activates ________.
Phospholipase C
How is Phosphatidylinositol 4,5 bisphosphate (PIP 2) activated by ATP and kinases?
Kinases catalyze sequential transfer Phosphate group (Pi) from ATP to hydroxyl groups at positions 5 and 4 of the inositol ring of phosphatidylinositol (in membrane)
Cleavage of PIP 2 (phosphatidylinositol 4,5 bisphosphate) in the inner leaflet by _________ yields 2 second messengers : _________ and _________.
- Phospholipase C (cleaves phospho bonds)
- Inositol 1,4,5-trisphosphate (IP3)
- Diacylglycerol (DG)
What is the common role for Inositol triphosphate ? (IP3 or Inositol 1,4,5,-tris phosphate)
- broken off from PI 4,5, bis-phosphate by a Phospholipase C-isoenzyme (generates IP3 and DAG)
- Floats around as second messenger
What is Phospholipase C activated by ?
Heptahelical receptor-G-protein signal transduction pathway
What does Phospholipase C (PLC) cleave PI-4,5,-bisP after it was phosphorylated from Phosphotidylinositol by kinases that phosophoryated the inositol ring at 4 and 5 positions ?
DAG
Inositol 1,4,5,-tris-phosphate (IP3)
BOTH SECOND MESSENGERS
What can PI 4,5,-bis-phosphate be turned into besides IP3 and DAG? and by who?
PI-3 Kinase (Phosphotidylinositol 3’ kinase) to form PI 3,4,5-trisP
-Forms membrane docking sites for proteins with
PLECKSTRIN HOMOLOGY DOMAIN
What can catalyze the dephosphorylation of PI3,4,5,-trisP ?
Phosphatase and tensin homolog (PTEN)- removes primary signal from pathway
-Mutation or Mis-expression of PTEN can lead to cancer
If a protein has an SH2 Domain, what does this allow it to do?
Dock to phosphorylated Tyrosine residues on proteins - to then likely be activated themselves
What is a Pleckstrin Homology domain for if a protein has it?
Good for targeting cellular membranes by binding specifically to phosphoinositides
What is the role of Mitogen activated protein kinase cascades? (MAP-K)
Directing cellular response to diverse stimuli - osmotic stress, heat shock, proinflammatory cytokines
-regulate proliferation, gene expression,differentiation , mitosis, apoptosis
What effect does insulin have on cAMP concentration?
Lowers cAMP by causing phosphodiesterase activation
What are some functions of cAMP?
- Allosteric activator of protein kinase A (PKA)- for rapid response to hormones such as epinephrine and glucagon
- Slower response pathway-gene transcription through CREB
What are three examples of things that can cross the cell membrane through diffusion?
Gases: such as Oxygen and CO2
Lipid Soluble substances like steroid hormones
What is the Cystic Fibrosis Transmembrane Conductance regulator (CFTR) an example of ?
Chloride channel that is an example of a ligand-gated channel regulated through Phosphorylation
(Needs ATP to open as well)
-Simple Diffusion channel
Patients with Type 1 diabetes have a decreased ability to transport _____ into tissues, thereby contributing to _______.
Glucose
Hyperglycemia (high blood glucose)
Which Ion K+ or NA+ has which concentration in the cell and ouside?
[K+] is higher inside the cell
[Na+] is higher outside the cell
Describe how the Na+-K+ ATPase (active transport) pump works?
3 Na+ ions bind on inside cell side of transporter (carrier)
ATP is hydrolyzed to ADP the carrier is phosphorylated-conformational change
Releases Na+ extracellularly , then 2 K+ ions bind
-Carrier is Dephosphorylated and that causes the K+ to be pulled inside with another conformation change back to original state of carrier shape
Describe the main process of secondary active transport with the Na+-Glucose transporter?
- A Na+ ion binds on Lumen side of membrane with 1 Glucose to carrier protein (inside of GI tract where food is)- Glucose moves against gradient into cell with Na+
- Carrier releases Na+ and Glucose into cell
- Sodium-Potassium pump sends Na+ back out to extracellular fluid to keep concentration low inside cell
- Glucose moves with passive diffusion once in cell to extracellular fluid on passive transporter protein
What are examples of passive transport?
Water Gases - Oxygen, CO2 Steroids (Lipid soluble substances) Voltage-Gated channels- with gradient Anything moving with its gradient
What are 2 examples of active transport?
Na+-K ATPase pump (maintains low Na+ intracellular concentration)
Ca+2-ATPase pump (maintains low Ca+ intracellular concentration - if fails cell can die)
What is an example of facilitated diffusion via channel or carrier?
Cystic Fibrosis transmembrane conductance regulator (CFTR)
-needs ATP to phosphorylate to open channel, but then Cl- will diffuse through simple diffusion
How do enzymes in the Lysosome mainly cleave amide, ester and other bonds?
Through hydrolases- adding water
What is the optimal pH for Hydrolases in the lysosome?
- 5
- Vesicular ATPases will pump in protons to keep the pH low inside the lysosome compared to the pH in the cell of 7.2
What are two examples of Secondary active transport?
Glucose-Na+ transport
Pyruvate + electron transport into Mitochondria (electron is going with gradient and Pyruvate against gradient along for the ride)
Where is Phosphotidylserine located ? net charge at pH 7.5 ?
Inner leaflet
negative charge
What is the plasma membrane composed mostly of ?
Phospholipids and Cholesterol
True or False:
Phospholipids are amphipathic (contain polar and non-polar ends)
True
Where are the Fatty Acyl groups on the phospholipid?
Facing eachother on inside of bilayer membrane
Where are the polar oligosaccharide groups of glycoproteins and glycolipids for plasma membrane?
Extending into aqueous medium outside and inside cell
What does DAG stand for ?
Diacylglycerol
What does the hormone Glucagon stimulate on liver parenchymal cells?
Glycogenolysis - Stimulates release of glucose from glycogen stores
- Endocrine hormone
- only stimulates in tissue with Glucagon receptors (like liver) - skeletal muscle does not have receptors for it
What two types of messengers does the Nervous system secrete?
- Biogenic amines (nitrogen containing molecules- usually contain amino acids or derivatives ACh, Epinephrine)
- Neuropeptides -(4-35 amino acids-small) at synaptic junctions or in blood as neurohormones
Where does Insulin come from ? what type of hormone?
Secreted from Beta cells of pancreas
-Endocrine hormone that travels in blood to target cells
(Polypeptide hormone)
What are the classes of endocrine hormones?
Polypeptide hormones (insulin) Catecholamines (epinephrine- also neurotransmitter) Steroid hormones (derived from cholesterol) Thyroid Hormones (derived from Tyrosine)
What are two compounds difficult to classify but are usually classified as hormones even though they are not synthesized in endocrine cells?
Retinoids - Derivatives of Vitamin A
Vitamin D - Derived from Cholesterol
What do Eicosamoids do? examples?
Prostaglandins, thromboxanes, leukotrienes
- Control cellular function in response to injury
- derivatives of arachidonic acid, 20 Carbon polyunsaturated fatty acid in membrane
What types of polar molecule messengers can not rapidly cross the membrane and must bind to a plasma membrane receptor?
Peptide hormones
Cytokines
Catecholamines
What are four examples of Lipophilic Hormones that use intracellular gene-specific transcription factors?
Steroid hormones
Thyroid hormones
Retinoic Acid (Active form Vit A)
Vitamin D
What do the four examples of Lipophilic hormones use to travel in blood?
Serum Albumin - has a hydrophobic binding pocket
or more specific:
Steroid-hormone binding globulin(SHBG)
Thyroid-hormone binding globulin(TBG)
The members of steroid/thyroid hormone receptors are mainly on the nucleus of cells, but what is the example of the receptor that is in the cytoplasm?
Glucocorticoid receptor - associated with Heat-shock proteins in cytoplasm
what are the two main types of effects on the cell from membrane receptors?
- rapid immediate effects on cellular ion levels or activation/inhibition of enzymes
- (and/or) slower changes in the rate of gene expression for a specific set of proteins
What does STAT stand for in the Jak-STAT receptor pathway?
Signal transducer and activator of transcription
Describe Ras? what pathways is it found in?
A membrane bound monomeric G-protein that is located in the plasma membranse
in the Ras-MAP kinase pathway for Tyrosine Kinases
(Protein-Protein pathway)
What is another name for the Raf protein that binds to Ras (that is in the membrane) when Ras is activated by GTP ?
MAPKKK (Mitogen-activated protein kinase kinase kinase
What does Raf do once activated (Tyrosine-kinase pathway)?
Initiates phosphorylation cascade (MAP kinase cascade)
-leads to alternation of gene transcription activity up or down for many genes involved in cell survival and proliferation
A signal transducer protein may only be specific for one type of receptor even though many have similar SH2 domain because _____.
Each Phosphotyrosine residue on receptor is surrounded by different amino acid sequence that forms specific binding domain (however one Grb2 can still bind to multiple receptors at once - just of the same type)
Tyrosine Kinase receptors and heptahelical receptors have additional pathways involving intermediates such as _______.
Phosphotidylinositol phosphates (in signal transduction)
True or False:
Phosphotidylinositol signaling molecules can be generated through either Tyrosine kinase receptors or heptahelical receptors.
True
Phospholipase isozyme C (cleaver) of Gamma type is activated by which type of pathway? and is associated with what?
Tyrosine Kinase growth factor pathway receptors
Phospholipase isozyme C (cleaver) of Beta type is activated by what ?
Heptahelical receptor-G protein signal transduction pathway
What is different about the Insulin pathway from other growth factor receptors?
Exists in the membrane as a preformed dimer, with each half containing an alpha and beta subunit
-alpha is external
beta is internal side of cell
In the insulin pathway , when Grb2 binds, it activates Ras and the ______.
MAP kinase pathway
What are the three site pathways that the IRS when phosphorylates will trigger? (can still trigger other intermediate pathways too )
- Grb2 to MAP Kinase pathway
- Phosphotidylinositol 3’ kinase (PI-3 kinase) binds to IRS and is activated - goes over to create pleckstrin homology domains
- Phospholipase C-Gamma (PLC- Gamma) binds and is activated -goes to intermediate pathway to make DAG and IP3
What does the activation of PI-3 kinase do in the insulin pathway?
activates movement of Protein Kinase B (PKB- serine-threonine kinase) and phosphoinositide-dependent kinase 1 (PDK-1) that will mediate many down stream effects of insulin
-PH domains will bind to PI-3 kinase on each
PDK-1 phosphorylates and activates what once is bound to Phosphotidylinositol 3-kinase ?
Protein Kinase B (PK-B)
What are Jak-STAT tyrosine-kinase-associated family receptors used for mainly ?
Proliferation of certain cells in Immune response
- have more direct route to signal the nucleus than normal tyrosine-kinase receptors
What is another name for Protein Kinase B ?
Akt
What are the two main types of regulation of the Jak-STAT pathway?
- Suppressors of cytokine signaling (SOCS)-first messenger level
- Protein inhibitors of activated STAT (PIAS)- second messenger level
Proteins in the transforming growth factor superfamily receptors that have :__________
Serine-Threonine kinase activity and associate with proteins from the Smad family (gene specific transcription factors)
What is Transforming growth factor Beta (TCF-Beta) involved in ?
Serine-threonine kinase activity pathway
-cytokine/hormone for tissue repair, immune regulation, cell proliferation, bone morphogenetic proteins (control proliferation, differentiation, death during development)
What is the Smad 4 ?
the Common Smad or Smad 4 or “co-Smad” that is not phosphorylated and forms a complex with the Smad that dissociated from the Type 1 TGF-Beta receptor
How is Smad regulated through signal termination ?
Inhibitory Smad complex
What are the G-alpha subunits that inhibit adenylyl cyclase called ?
G-apha -i
What hydrolyzes cAMP to AMP ?
cAMP phosphodiesterase (resides in membranse like adenylyl cyclase does)
How are concentrations of cAMP kept at low levels ?
balancing cAMP phosphodiesterase vs adenylyl cyclase - so that cAMP levels can change rapidly when hormone levels change
How does insulin regulate cAMP levels ?
Lowers cAMP levels by causing cAMP phosphodiesterase asctivation (turns cAMP into AMP)
What function does IP-3 have in cell after activation and dissociation ?
binding site in sarcoplasmic reticulum and the endoplasmic reticulum that stimulates the release of Ca(2+) - activates enzymes containing the calcium-calmoduln subunit (including a protein kinase)
What does DAG do while staying in the membrane ?
activates protein kinase C, which then propogates the response by phosphorylating target proteins
Describe how down-regulation works ?
Receptor number is reduced by after binding, during excess hormone signal, the receptor may be taken in by endocytosis in clathin-coated pits - then degraded or recycled back to cell surface (decreases number of receptors avaliable for activation)
What are two examples of termination of signal at the first messenger or signal level ?
- Insulin (or many polypeptide hormones) are taken up into liver and degraded.
- Termination of ACh signal by Acetylcholinesterase
What are 2 examples of signal termination at the receptor level ?
- Serpentine receptors can be desensitized to messenger by phosphorylation, internalization, degradation
- G-proteins will automatically terminate messages as they hydrolyze GTP via their intrinsic GTPase
Besides termination at the receptor or primary messenger level, what is another termination pathway?
used by receptor kinases through protein phosphatases, enzymes that reverse the action of kinases
- one exists for every kinase that exists specific to it
- Receptors themselves can exhibit protein phosphatase activity
What can Epinephrine do (a catecholamine released when exercising) for metabolism ?
promotes fuel mobilization for utilization
Nitric oxide is able to diffuse into the cell (gas) and is a __________ , that will bind to receptor _____.
neurotransmitter/neurohormone
guanylyl cyclase that is floating in cytoplasm -
(this is the exception to the rule that intracellular receptors are always gene transcription factors)
Membrane bound guanylyl cyclase receptors convert GTP to the second messenger ________ that is analougous to cAMP.
3,5,-cyclic GMP (cGMP)
the receptors for guanyly cyclase are different from heptahelical receptors because they ________.
Do not require g-protein signaling to adenylyl cyclase, but directly produce cGMP
What does cGMP do ?
elevated levels will activate protein kinase G which phosphorylates target proteins for a response
(treat heart failure, ED, angina pectoris through drugs that inhibit cGMP phosphodiesterase so that cGMP levels stay high)
