MCBL: Cell Signaling & Communication I Flashcards
What are signaling molecules used for?
Signaling molecules are used within an organism to control organismal functions.
What is a receptor?
A receptor is a protein that sits at the surface (or sometimes the interior) of a cell and it responds to the binding of a ligand (signaling molecule).
True or False: Receptors and ligands are specific for one another.
True; Receptors have high affinity for their ligands.
True or false: The concentration of ligands is usually low.
True
What does the term ‘signal transduction’ refer to?
Signal transduction refers to the overall process of converting extracellular signals into intracellular responses.
What are the different types of cell-to-cell communication modes?
a) Contact dependent
b) Paracrine
c) Synaptic
d) Endocrine
What is contact dependent cell signaling?
This is a type of signaling where one cell has a membrane bound signaling molecule and it binds directly to a receptor on a target cell.
This is important in development and immune system responses.
What is paracrine signaling?
Paracrine signaling involves the signaling molecule being released by a cell and the molecule only effects cells in close proximity.
What is autocrine signaling?
This is a form of signaling whereby cells respond to substances that they release themselves.
What is endocrine signaling?
Endocrine signaling involves the realase of a signaling molecule by an endocrine cell. The molecule travels through the blood and acts on a target cell that is distant from the endocrine cell.
What is synaptic signaling?
Synaptic signaling involves a nerve cell that synapses on a target cell (A form of contact-dependent signaling) that is some distance away from the nerve cell. Neurotransmitters are released across the synaptic cleft and bind to receptors on the target cell and bring about some change within the cell.
What do “signaling kinetics’ refer to?
Signaling kinetics refers to the speed with which an extracellular signaling molecule causes some action to take place within the cell.
If the signal directly results in altered protein function, this is fast, sec to minutes.
If the signal must cause transcription and translation to generate altered proteins, this is slow, minutes to hours.
In both cases, the end result is altered cell behavior.
True or false: One cell can respond to and interpret different types of signals.
True; each cell type displays a set of receptors that allow it to respond to a corresponding set of signaling molecules.
These signaling molecules work in combinations to regulate the behavior of the cell.
True or false: The same type of signaling molecule (Ach for example) can have multiple responses in different cell types.
True; one signaling molecule can alicit different responses depending on the signaling pathway and receptor type.
True or false: The concentration of signaling molecule can produce different responses within a given cell.
True
What determines the rate of the ‘on’ and ‘off’ function of a signaling pathway?
The half-life of the signaling molecule.
The half-life is the rate of synthesis and degredation of a given molecule.
What is the role of nitric oxide gas and where is it produced?
NO is a local signal.
It is activated by the release of Ach; in response to the release of Ach, NO is produced by endothelial cells
What does NO act on?
NO diffuses out of cell and into smooth muscle where it binds to and activates guanylyl cyclase to produce GMP
What does GMP do?
GMP causes smooth muscle relaxation to enhance blood flow
Picture of nitric oxide action on guanylyl cyclase.
What are nuclear receptors?
Nuclear receptors are intracellular ligand gated modulated gene regulatory proteins.
The signal molecules for nuclear receptors are small and hydrophobic; bind to carrier proteins in body fluid.
What is an orphan nuclear receptor?
These are receptors that have been identified by their DNA sequence without knowing what the ligand is.
Describe the nuclear receptor superfamily.
Made up of receptor dimers that bind to specific DNA sequences that are adjacent to geners that are regulated by the receptors ligand
Some nuclear receptors in this family are located in the cytosol and only enter the nucleus after ligand binding
Others are bound to DNA in the nucleus
What is meant by the term ‘Nuclear receptor induced direct and indirect responses’?
This term refers to the ability of a signaling molecule-receptor complex to either bind directly to DNA and induce a response directly or the ability of a signaling molecule to activate another pathway that will induce a DNA response within a cell.
What are the three major classes of cell-surface receptors?
Ion channel - Gated or ionotropic
G-protein coupled receptors - Mediated by a trimeric GTP-binding protein
Enzyme coupled receptors - Possess active catalytic domains
What are second messengers?
These are small intracellular signaling molecules.
They are activated by a “First” messenger that binds to the extracellular cell surface receptor
Examples of 2nd messengers include cAMP, Ca2+ , diacyclglycerol
What is a relay protein?
Relay proteins pass on a message.
What are adaptor/scaffold/anchor proteins?
These are proteins that link a signaling protein to other proteins without themselves conveying a signal.
What is an amplifier protein?
These are enzyme of ion channels that greatly enhance the signal that they receive.
What is a transducer protein?
A transducer protein is one that converts the signal into different forms.
What is a bifurcation protein?
These proteins spread the signal from one signaling pathway to another.
What is an integrator protein?
These proteins receieve signals from two or more signaling pathways and integrate them into one signal before passing them on.
What are modulatory proteins?
These proteins modulate the activities of other signaling proteins.
What is a molecular switch?
A molecular switch is a molecule that can turn a pathway on or off.
How do phosphorylation cascades act as molecular switches?
A protein kinase phosphorylates the next protein kinase and tis amplyfies the signal and spreads it to other pathways.
Serine/threonine and tyrosine kinases are the major kinases
ATP is hydrolyzed to ADP and this turns the signaling pathway on.
When The signal molecule is dephosphorylated, the pathway turns off
How do GTP-binding proteins play a role as molecular switches?
A signal comes into the cell that brings about a GTP being exchanged for GDP. This turns the pathway on.
When GTP is hydrolyzed to GDP, the pathway turns off.
GDP stays bound to the original signaling molecule.
How do stable cell signaling complexes relate to the speed and efficiency of cell signaling?
Stable complexes form with scaffold proteins that guide interactions among different signal molecules.
This provides a platform for precision, speed, and efficiency.
Scaffold proteins also prevent unwanted cross talk between signalling pathways.
How do assembeled (non-stable) signal complexes relate to speed and efficiency in cell signaling?
These signalling complexes are transient and must be induced to form by some cell signal.
The component proteins form around the activated receptor.
These complxes are rapidly disassembled after the extracellular ligand dissociates from the receptor.
What is an adaptor protein?
A protein that acts as a connecting molecule. An adapter protein is critical to intermolecular interactions and plays a role in the regulation of signal transduction initiated by engagement of surface receptors on all cell types.
Describe the domains of adaptor proteins.
Src homology 2 (SH2) and phosphotyrosine binding domains (PTB) bind to phosphorylated tyrosines
Src homology 3 (SH3) binding domains bind to proline rich sequences
Pleckstrin homology domains (PH) bind to phosphoinositides
PDZ domains bind to PDZ binding domains
What is positive feedback?
Positive feedback, as it relates to cell signaling, occurs when a signaling molecule causes a receptor to cause some action. The products of this action then “feedback” into the loop to enhance the activity of the receptor and additional product is produced.
What is negative feedback?
Negative feedback, as it relates to cell signaling (and kinase activity) occurs when a stimulus causes the receptor/kinase to undertake some action. The products of this action then inhibit further action by the receptor / kinase.
What is receptor sensitivity regulation?
This is a means for the cell to control its sensitivity to an outside stimulus.
Receptor sequestration
Receptor downregulation
Receptor inactivation
Inactivation of signaling protein
Production of inhibitory protein
True or False: G proteins constitute the largest gene family in the human genome.
True; GPCRs constitute more than 1000 genes
They are the target of the majority of the best selling prescription drugs on the market
They are the most numerous receptor in mammals
Describe trimeric G protein coupled receptors.
Trimeric G proteins are made up of three subunits: alpha, beta and gamma
The alpha subunit has GTP/GDP binding activity
20 alpha genes, 6 beta genes and 11 gamma genes; leads to 1400 alpha, beta, and gamma combinations
When inactive, GDP is bound to the alpha subunit
Ligand binding to the GPCR (functions as a GEF) leads to an excahnge of GDP for GTP to activate alpha subunit and induce a conformational change
G alpha and G beta-gamma acctivate various effectors
Describe the inactivation of trimeric G proteins.
The alpha subunit has GTPase activity
It hydrolyzes GTP to GDP
GTPase activity is enhanced by binding to target protein or regulator protein
There are about 25 g protein regulator proteins encoded in the human genome; these react with a particular G protein
Picture describing G protein coupled receptor activation and inactivation.
True or false: Do G proteins regulate the production of cAMP?
True; cAMP is synthesized from ATP by membrane bound adenylyl cyclase
cAMP is destroyed by cAMP phosphodiesterases
Adenylyl cyclase has multi-transmembrane domains with its catalytic domain on the cytosolic face; 8 isoforms in mammals that are regulated by G proteins and Ca2+
Adenylyl is activated by stimulatory G protein (GS ) but inhibited by inhibitory G protein (GI )
What is the relationship between cAMP and Protein Kinase A (PKA)?
PKA is a serine/threonine kinase
; has two catalytic subunits and two regulatory units
Binding of cAMP to the regulatory subunits causes them to dissociate from tthe catalytic subunits
Activated PKA then phosphorylates its targets (CREB) and this eventually leads to gene transcription once the gene is bound by a cAMP response element binding protein (CREB)
Transcriptional coactivator CREB binding protein binds to the phosphorylated CREB and stimulates gene transcription
Picture of PKA and cAMP signaling.
Picture of G protein coupled receptor and adenylyl cyclase signaling.
Picture of G protein activation of phospholipase C-beta.
True or false: Ca2+ serves as a intracellular mediator.
True; Three types of Ca2+ channels mediate calcium signaling
Ca2+ channels in the plasma membrane
IP3-gated Ca2+ channels on the ER membrane
Ryanodine receptors on the sarcoplasmic and endoplasmic reticulum
Ca2+ concentration kept low in cytosol via pumps, carriers and binding proteins
How are calcium oscillations formed in the cell?
Initial Ca2+ release induces more calcium release. This higher calcium concentration leads to a reduction in calcium release.
Calcium sensitive proteins change their activity as a function of this calcium release
Picture of Ca2+ / Calmodulin-dependent protein kinase (CaM Kinase) activation.
Calmodulin is a multipurpose Ca2+ receptor w/ 4 high affinity Ca2+ binding sites
Responds in a positive feedback manner to increased concentrations of Ca2+
Calmodulin has no enzymatic activity
Binding of the CaM kinase to target changes conformation and activity
Picture of G protein coupled receptors in cAMP-gated ion channels in smell sensation.
Picture of G protein activation of adenylate cyclase subunit.
Describe what happens during visual transduction. How are GPCR’s related to this process?
When light hits rhodopsin, GTP is exchanged for GDP on the alpha subunit of the GPCR (G protein transducin).. Light causes the cell membrane to become hyperpolarized.
The GTP-bound alpha subunit binds to and activates cGMP phosphodiesterase (PDE)
PDE then hydrolyzes cGMP to reduce its concentration
This in turn leads to a closure of Na+ channels and the influx of Na+ ions ceases.
How are GPCR’s desensitized?
Active GPCR’s stimulate GRK to phosphorylate the GPCR at multiple sites by a GPCR kinase, PKA, or PKC
Arrestin will then bind to the phosphorylated GPCR
Receptor is either internalized and recycled or degraded in lysosomes
