Flashcards in BIOL 0800 Reading- Chapter 5 Deck (100):
What is the first step in the action of any intercellular chemical messenger?
The binding of the messenger to specific target cell proteins known as receptors or receptor proteins
What is a receptor or receptor protein?
A specific target cell protein to which the messenger binds during intercellular chemical messaging
What is a chemical messenger?
What is signal transduction?
The sequence of events caused by the binding of a messenger to a receptor protein that leads to the cell's response to that messenger
What are the receptors that intercellular chemical messengers bind to?
Proteins or glycoproteins in the plasma membrane or cytosol or nucleus (usually the plasma membrane)
Why are the majority of receptors located in the plasma membrane?
Because the messengers are usually water soluble and can't diffuse across the lipid membrane
What is a receptor "superfamily?"
When receptor proteins for a group of messengers are structurally related, like for hormone receptors
If different types of cells have the same receptors for a particular messenger, does that messenger affect each of the cells the same way?
Nope: norepinephrine contracts certain blood vessel smoother muscle cells, but decreases insulin secretion of certain pancreatic endocrine cells
Why do some cells contain more than one difference receptor type for a single messenger?
Because the different types of receptors can have different effects on the cell even with the same messenger binding to them
What is affinity for a messenger?
The degree to which a particular messenger binds to its receptor
How does affinity affect binding?
High affinity means that the messenger will bind even at low concentrations, and low affinity requires high concentrations for binding
What is messenger saturation?
The degree to which receptors are occupied by messengers; if all are occupied, the receptors are fully saturated.
What is messenger competition?
The ability of different molecules to compete with a ligand for binding to its receptor; competitors generally are similar in structure to the natural ligand
Competition between what kind of messengers occurs most frequently, and what is this the basis for?
Closely related messengers, and underlies the action of many drugs
What are antagonists?
Drugs that block the endogenous messenger from binding but don't trigger the cell's response; example is beta blockers
What do beta blockers do?
Use epinephrine and norepinephrine to bind for receptors involved in high blood pressure and other diseases (beta-adrenergic) to prevent an increase in blood pressure that would have resulted from the epinephrine/norepinephrine
List two common antagonists.
Beta blockers and antihistamines
What are agonists?
Drugs that bind to a particular receptor type that do trigger the cell's response exactly as if the endogenous messenger had been bound
List one common example of use of agonists.
Phenylephrine or oxymetazoline decongestants that mimic the action of epinephrine to induce vasoconstriction in the nasal passages.
What is down regulation?
A decrease in the total number of target-cell receptors for a given messenger; mat occur in response to chronic high extracellular concentration of the messenger
What is a colloquial word for down regulation?
What is up regulation?
An increase in the total number of target cell receptors for a given messenger; mat occur in response to a chronic low extracellular concentration of the messenger
What is internalization and what does it affect?
When the entire receptor complex is taken in by endocytosis after the messenger binds, which increases degradation of the receptor and leads to down regulation
What is receptor activation?
The initial step leading to a cell's responses to the messenger, where the biding of the messenger to the receptor causes a change in the receptor's conformation
What are the five cellular responses that can constitute the changes in conformation of the receptor during receptor activation?
Permeability, transport properties, or electrical state of the plasma membrane; metabolism; secretory activity; rate of proliferation and differentiation; contractile or other activities
What is the "common denominator" to the variety of responses to receptor activation?
They're all directly due to alterations of particular cell proteins
What are signal transduction pathways?
The diverse sequences of events between receptor activation and cellular responses
What kinds of receptors are inside the cytosol rather than in the plasma membrane?
Receptors for lipid soluble messengers, because those can pass through the membrane
How do lipid soluble messengers generally act on cells?
Binding to intracellular receptor proteins
What are some examples of lipid soluble messengers?
Steroid hormones, thyroid hormones, steroid derivative 1,23-dihydroxy vitamin D
What is the steroid hormone receptor superfamily?
The receptors for the steroid/thyroid/1,25-dihydroxy vitamin D messengers
Where are most of the inactive receptor in the steroid hormone superfamily residing in the cell?
Already in the cell nucleus where they bind to and are activated by their respective ligands
What does receptor activation of the steroid hormone superfamily in the cell nucleus activate?
Altered rates of gene transcription
What does the activated receptor complex for the steroid hormone superfamily function as in the nucleus?
A transcription factor, which is any regulatory protein that directly influences gene transcription
Where does the hormone-receptor complex bind in the GNA for the steroid hormone superfamily?
Near a gene in DNA called a response element, which increases the rate of the gene transcription in mRNA
What is a response element?
A specific sequence near a gene in DNA
What is the general phrasing for the effect of the transcription factor by the binding of steroid hormone superfamily receptors to their ligands in the cell nucleus?
Faster transcription which results in proliferation of the particular protein encoded in that gene segment
Does activation of the transcription factor by activation of the steroid hormone superfamily complexes always results in increased transcription rates?
Nope, can also result in decreased, like hoew cortisol decreases transcription to mediate inflammatory responses that occur after injury or infection
Can more than one gene be subject to control by a single receptor type?
Yes: glucocorticoid hormone cortisol acts via one type of receptor to activate various genes for cellular metabolism and energy balance
What are some examples of water soluble messengers?
Most hormones, neurotransmitters, and paracrine-autocrine compounds
What are the four types of plasma membrane receptors?
1) Receptors that are ligated gated ion channels; 2) receptors that themselves function as enzymes such as receptor tyrosine kinases; 3) receptors that are bound to and activate cytoplasmic janus kinases; 4) g-protein-coupled receptors that activate G proteins which in turn act on effector proteins, either ion channels or enzymes, in the plasma membrane
What are first messengers vs second messengers?
First messengers are the intercellular chemical messengers that reach the cell and bind to their receptors; second messengers are substances that enter or are generation as a result of first messenger receptor activation
What is a protein kinase?
An enzyme that phosphorylates other proteins by transferring a phosphate group to them from ATP
How do ligand-gated channels function?
Activation of the receptor by the first messenger opens the channel in the plasma membrane to increase net diffusion of the ions specific to that channel across the membrane
What kinds of cells feature a lot of ligand-gated ion channels?
Most of the receptors that possess intrinsic enzyme activity are what?
What kind of kinases are the majority of protein kinases that act enzymatically to facilitate water-soluble messenger pathways? Why?
Receptor tyrosine kinases, because they specifically phosphorylate the portions of proteins that contain the amino acid tyrosine
How do receptors with intrinsic tyrosine kinase activity function in water-soluble messenger pathways?
Messenger-receptor binding changes the conformation of the receptor so that the enzymatic portion is activated (on the cytoplasmic side), which autophosphorylates the receptor (receptor phosphorylates its own tyrosine groups); then the new phosphotyrosines on the cytoplasmic side are docking sites for cytoplasmic proteins, which bind and activate other proteins and so on and so on
What does autophosphorylation mean during the activation of the enzymatic portion of the receptor tyrosine kinase?
That the receptors own tyrosine groups get phosphorylated to create phosphotyrosines on the cytoplasmic side of the receptor
What is the common denominator of the pathways activated by receptor tyrosine kinases activated by their water-soluble messengers?
They all involve activation of cytoplasmic proteins by phosphorylation
Why are most receptors with intrinsic tyrosine kinase activity called growth factors?
Because they often influence cell proliferation and differentiation
What is the one major exception to the generalization that plasma membrane receptors with inherent enzyme activity function as protein kinases?
When the receptor functions as a receptor and as a guanylyl cyclase to catalyze formation of cyclic GMP (cGMP) that acts as a second messengers to activate a protein kinase called cGMP-dependent protein kinase that phosphorylates specific proteins to mediate the cell's response to the original messenger
What is the main difference between receptors with intrinsic enzyme activity and receptors that interact with cytoplasmic janus kinases?
In the former, the enzymatic activity resides in the receptor itself, but I JAK, it resides in a family of separate cytoplasmic kinases called janus kinases associated with the receptor
How does receptor activation with janus kinases work?
The first messenger binds to the receptor and causes a conformational change in the receptor that leads to activation of the janus kinase; the janus kinase associated with that receptor phosphorylates target proteins to act as transcription factors, which ends in the synthesis of new proteins
What is one example of signals mediated primarily by janus-kinase related receptors?
Cytokines: proteins secreted by cells of the immune system
What is the largest category of plasma membrane receptors?
What is a G-protein-coupled receptor?
The receptor in the plasma membrane has a protein complex bound to it on the cytosolic side (from the heterotrimeric protein family, G proteins) that can bind GDP and GTP
What are G-proteins?
Heterotrimeric (contain three different subunits); contain alpha, beta, and gamma subunits; alpha subunit can bind GDP and ATP; the beta and gamma subunits help anchor the alpha subunit in the membrane
What happens in g-protein-coupled receptors when the first messenger binds to the receptor?
Activated receptor increases the affinity of the alpha subunit for GTP, so they bind and the alpha subunit dissociated from the beta and gamma subunits, allowing the alpha subunit to link up with another plasma membrane protein (ion channel or enzyme) to mediate the next steps in the sequence
What are plasma membrane effector proteins?
Proteins in the plasma membrane (ion channels or enzymes) that are activated by the alpha subunit of the G protein (in the plasma membrane from the G-protein-coupled receptor) which has bound to GTP
What is the essence of the G-protein-coupled receptor's function?
It's a switch to couple a receptor to plasma membrane effector protein (ion channel or enzyme)
What happens are the alpha subunit of the G protein activation its effector protein?
A GTPase activity in the alpha subunit cleaves CTP into GDP plus Pi, rendering the alpha subunit inactive and recombining it with the beta and gamma subunits
What are two of the most important effector protein enzymes regulated by G proteins?
Adenylyl cyclase and phospholipase C
How does the adenylyl cyclase pathway work?
Activation of the receptor activates the associated G protein (here Gs for stimulatory), which activates its own effector protein, adenylyl cyclase in the membrane, which catalyzes the conversion of cytosolic ATP to cyclic AMP (3'5'-adenosine monophosphate), which is a second messenger
How does the action of cAMP terminate?
When it's broken into AMP by cAMP phosphodiesterase
How is the cellular concentration of cAMP changed?
By altering the rate of its messenger-mediated generation, or by altering the rate of its phosphodiesterase-mediated breakdown (caffeine and theophylline inhibit phosphodiesterase activity and breakdown)
What does cAMP do in cells?
Bind to and activates cAMP-dependent protein kinase (protein kinase A) which phosphorylates other proteins
What is the essence of activation of adenylyl cyclase by a G protein?
Initiates and amplification cascade of events that convert proteins in seuqnece from inactive to active forms
True or false: activation of one molecule of adenylyl cyclase may catalyze the generation of 100 cAMP molecules
True! And at the next step, there's another 100-fold amplification
What biological principle is illustrated by the amplification effect of activation of adenylyl cyclase?
How hormones and other messengers can e effective at extremely low extracellular concentrations
What does it mean for a gene to be cAMP-response?
That, when the cAMO-activated protein kinase A diffuses into the cell nucleus, it can phosphorylate a protein that binds to a specific regulatory region of the gene
How can cAMP's activation of a single molecule (cAMP-dependent protein kinase) result in so much variety?
cAMP-dependent protein kinase can nphosphorylate a large number of different proteins, so it can exert multiple actions within a single cell and different actiosn in different cells
Give an example of how cAMP-dependent protein kinase can have different effects in different cells.
Epinephrine activates the cAMP pathway in fat cells to break down triglycerides, but also in the liver to stimulate glycogenolysis and gluconeogenesis using different phosphorylated enzymes from the ones in fat cells
True or false: some receptors for first messengers, when activated, inhibit adenylyl cyclase.
True: results in less generation of cAMP because the receptors are associated with a different G protein, Gi (inhibitory), so decreases phosphoryltaion of key proteins in cells
What happens in the phospholipase C pathway?
G protein called Gq is activated by a receptor bound to the first messenger, which activates a plasma membrane effector enzyme called phospholipase C, to catalyze the breakdown of a plasma membrane phospholipied called phosphatidylinositol bisphosphate, PIP2, to diacylglycerol (DAG) and inositol trisphosphate (IP3)
What does the plasma membrane effector enzyme phospholipase C do?
Breaks down PIP2 into DAG and IP3, which function as second messengers In different ways
How does DAG from PIP2 act as a second messenger?
Activates protein kinase C (family) that phosphorylates a large number of other proteins
How does IP3 from PIP2 act as a second messenger?
Binds to receptors on the ER (ligand-gated Ca2+ channels), causing Ca ions to diffuse into the cytosol, increasing cytosolic Ca ion concentration, which THEN triggers the sequence of pathway events in response to the first messsenger
What is one of the most important features of G-protein function?
Its ability to both directly and indirectly gate ion channels
What does indirect G-protein gating of ion channels utilize?
A second messenger pathway for the opening/closing of the channel
What kinds of protein kinases can participate in indirect G-protein gating of ion channels?
cAMP protein kinases, but also other protein kinases that are involved in signal transduction pathways
What are the three ways receptor activation influences ion channels?
The ion channel is actually part of the receptor, a G protein directly gates the channel, of a G protein gates the channel indirectly via a second messenger that is a protein kinase
What ion acts as a common second messenger in a variety of cellular responses to stimuli?
What kind of Ca ion concentration is maintained in the cytosol, and how?
Very very low, thanks to active transport system sin the plasma membrane and organelles
What does the large electorchemical gradient favor, in regards to Ca ion activity in the cells?
Favors diffusion of Ca ions into the cytosol via channels in the membrane and ER
How can Ca ions act as a second messenger?
1) in response to chemical stimuli via receptors, and 2) in response to electircal stimuli acting via voltage-gated calcium ion channels, or 3) binding to Ca-ion-sensitive channels in the ER to open them
What is calcium-induced Ca ion release?
When the extracellular calcium ions enter the cells via voltage gated channels and bind to sensitive channels in ER to open them and allow a lot of Ca ion from the ER to enter the cytosol
What are the mechanisms by which stimulation of a cell leads to an increase in cytosolic Ca ion concentration?
Opened ion channels in the plasma membrane; Ca release from ER by IP3 or Ca ions themselves, or active Ca transport out of cell inhibited by second messenger; or opening of voltage-gated channels
What is the common denominator of calcium ion actions?
Its ability to bind to various cytosolic proteins to activated their function
What is one of the most important proteins that Ca ions can bind to?
Calmodulin, in basically all cells, which activates or inhibits calmodulin-dependent protein kinases via phosphorylation
What are eicosanoids?
Molecules produced from polyunsaturated fatty acid arachidonic acid in the plasma membrane phospholipids
What is included in the eicosanoid family?
Cyclic endoperoxides, prostaglandins, thromboxanes, and leurotrienes
How are eicosanoids produced?
Phospholipase A2 is activated by messenger-receptor binding, and it splits arachidonic acid from the membrane phospholipids for metabolization by two pathways
What are the two pathways for metabolization of arachidonic acid after it's split from the membrane phospholipids by the enzyme phospholipase A2?
1) Cycooxygenase (COX), which forms other cyclic endoperoxides, prostaglandins, and thromboxanes. 2) the enzyme lipoxygenase to form leukotrienes
What happens to eicosanoids after they are produced?
Might be used as intracellular messengers, but more commonly released and act locally (paracrine and autocrine substances)
What do eicosanoids have a particular effect on?
Blood vessels and inflammation
How is arachidonic acid different from other second messengers?
Although it transduces a signal from a messenger and receptor to a cellular response, it's special because it also serves as a substrate to be converted into other products
What are nonsteroidal anti-inflammatory drugs?
NSAIDs, which block cyclooxygenase and thus block the synthesis of endoperoxides, prostaglandins, and thromboxanes to recuce pain, fever, and inflammation
What is the key event in termination of signal transduction pathways?
Cessation of receptor activation, particularly by a decrease in first messenger concentration