Cell Signaling Flashcards
Describe homeostasis
An internal state that’s constancy is maintained by regulatory physiological processes
How are physiological processes regulated?
+ and - feedback loops
Describe a basic feedback loop
An external stimuli causes a variation in an internal variable
a sensor organ senses the change and sends a signal to another organ
the effector organ causes a change that effects the internal state
What are the 2 types of cell signaling?
direct
indirect
Describe direct cell signaling
cells communicate directly to one another through gap junctions (ie., small hydrophilic signal molecules can be transported)
Define gap junctions
complexes of proteins that connect cytoplasms of 2 nearby cells (via connexins) to create an aqueous pore that is permeable to small hydrophilic molecules (ex. Ca2+, cAMP)
How do cells send hydrophilic signal molecules to one another given cell membranes are hydrophobic?
through gap junctions which are permeable to hydrophilic signal molecules
T or F: the movement of ions/small hydrophilic molecules through gap junctions affects the membrane potential
true
T or F: the opening/closing of gap junctions cannot be regulated
false, it can be regulated
What is commonly moved through gap junctions in direct signaling?
ions
Describe how the movement of ions through gap junctions act as a signal
they cause a change in membrane potential that causes a response in the target cell
T or F: direct signaling is rapid
true
At what level does direct signaling have the largest effect on regulating physiological responses?
tissues
Describe indirect cell signaling
the signaling cell releases a chemical messenger into the extracellular fluid
it then binds to a receptor on the target cell
chemical messenger binding to the receptor activates signal transduction or ion channel which triggers a response in the target cell
What are 4 types of indirect cell signalling?
paracrine
autocrine
endocrine
neural
What’s the main difference between the types of signaling?
their maximum signaling distance
Which types of cell signalling have short signaling distances?
- direct (the cell’s have to be directly adjacent)
paracrine and autocrine use diffusion to signal which is slow so max distances are short
Which types of signaling have longer maximum distances?
endocrine system which uses the circulatory system
nervous system sends long distance signals using electrical signals (action potential) within a single neuronal cell
How does the endocrine system transport signal molecules across long distances?
it uses the circulatory system to transport chemical messengers (hormones)
What are the chemical messengers that are transported as signals by the endocrine system?
hormones
How does the nervous system transport signal molecules across long distances?
the nervous system transports electrical signals (action potential) along a neuron to trigger the release of a chemical messenger (neurotransmitter) across a synapse to an adjacent cell
What are the chemical messengers transported as signals by the nervous system?
neurotransmitters
Describe paracrine signaling
a chemical messenger is released from the signal cell and diffuses to a nearby target cell
describe autocrine signaling
a chemical messenger released by the signaling cell diffuses BACK to the signaling cell and causes a response in the signal cell
What are the 3 steps of indirect signaling?
- chemical messenger released from signaling cell
- messenger is transported extracellularly to the target cell
- signal is communicated to target cell
What are the 7 types of chemical messengers?
peptides (ex. insulin, glucagon, atrial natriuretic peptide)
steroids (ex. testosterone, estrogen, aldosterone, cortisol)
amines (ex. norepinephrine, epinephrine)
lipids (ex. eicosanoids: prostaglandin, leukotrienes)
purines (ex. AMP, ATP, GMP)
gases (ex. nitric oxide)
amino acids (ex. glutamate, aspartate, glycine)
Describe peptide (protein hormones) as chemical messengers
made up of amino acids
synthesized on the rough ER (preprohormones)
stored in vesicles (prohormones)
exocytosis secretion
hydrophilic - travels to target cell dissolved in extracellular fluid
binds to transmembrane receptors and cause signal transduction
has rapid effects
What are peptides/protein hormones made from?
amino acids
Where are peptides/protein hormones synthesized?
on the rough ER
Where are peptides/protein hormones stored?
in vesicles
How are peptides/protein hormones secreted?
by exocytosis
Are peptides/protein hormones hydrophobic or philic? how do they travel to target cells?
hydrophilic - travel extracellularly
T or F: peptides/protein hormones have a slow response
false, they have a rapid response
How do peptides/protein hormones interact with the target cell? what is the response?
they bind to transmembrane receptors and activate signal transduction pathways
What are steroid hormones derived from?
cholesterol
Where are steroid hormones synthesized?
by the smooth ER or mitochondria
What are the 4 classes of steroid hormones ?
mineralocorticoids (aldersterone)
glucocorticoides (cortisol, corticosterone)
reproductive hormones (estrogen, progesterone, testosterone)
molting hormone (ecdysone)
What is the function of mineralcorticoids? what’s an example of these steroid hormones?
electrolyte balance by regulation of sodium uptake by the kidney
ex. aldosterone
What is the function of glucocorticoides? what’s an example of these steroid hormones?
these hormones function in stress responses
ex. cortisol, corticosterone
What is the function of reproductive hormones? what’s an example of these steroid hormones?
these steroid hormones regulate sex-specific characteristics
ex. progesterone, testosterone, estrogen
What is the function of molting hormones? what’s an example of these steroid hormones?
they function in the shedding of insect exoskeleton during molting
describe the derivation of glucocorticoids from cholesterol
cholesterol > prenenolone > progesterone > cortisol & corticosterone
describe the derivation of mineralcorticoids from cholesterol
cholesterol > prenenolone > progesterone > corticosterone > aldosterone
describe the derivation of reproductive hormones from cholesterol
cholesterol > prenenolone > progesterone > testosterone > estrogen
Are steroid hormones hydrophobic or philic? what does this mean for their transport?
hydrophobic - they can diffuse directly through the plasma membrane
T or F: steroid hormones can be stored in the cell
false
T or F: steroid hormones must be synthesized on demand
true
Why must steroid hormones be synthesized on demand?
because they cannot be stored in the cell
How are steroid hormones transported to target cells?
by carrier proteins (ex. albumin, globulins)
How do steroid hormones interact with target cells?
by binding to intracellular or transmembrane receptors
Are the effects of steroid hormones slow or rapid? why? what is one exception?
slow because they can function in processes like transcription and translation (genomic effects)
cortisol is an exception: has rapid non-genomic effects
Describe amine hormones
these are hormones that include an amine group (R-NH2, R2-NH, or R3-N)
What’s an amine group?
R-NH2 (mainly this one)
R2-NH
R3-N
What are some examples of amine hormones/biogenic amines?
acetylcholine
catecholamines (ex. dopamine, norepinephrine, epinephrine)
serotonin
melatonin
histamine
thyroid hormones
T or F: all amine hormones/biogenic amines are true hormones
false, some are, but some are neurotransmitters and some are both
Most amine hormones/biogenic amines are hydrophobic or philic? with what exception?
hydrophilic
exception: thyroid hormones are hydrophobic
What are the catecholamines? what are they synthesized from?
dopamine, norepinephrine, epinephrine
synthesized from tyrosine AA
T or F: dopamine exists in all animals
true
Is dopamine a true hormone?
no, it acts as a neurotransmitter
Are norepinephrine and epinephrine found in all animal taxa? what type of messenger do they act as?
no, only vertebrates
act as neurotransmitters, paracrines, and hormones
What animals are thyroid hormones found in? what type of messenger do these act as? what amino acid are they synthesized from?
only vertebrates
synthesized from tyrosine
act as hormones
What is serotonin synthesized from? what type of messenger does it act as? in all animals?
tryptophan AA
acts as a neurotransmitter in all animals
What is melatonin synthesized from? what type of messenger does it act as?
tryptophan
all animals
acts as a neurotransmitter and hormone
What is histamine synthesized from? what type of messenger does it act as? all animals?
synthesized from histidine
acts as a neurotransmitter and paracrine
in all animals
What is acetylcholine synthesized from? what type of messenger does it act as? all animals?
from choline (an amine that’s not an AA + acetyl-coenzyme A)
acts as a neurotransmitter
found in all animals
What type of messenger do eicosanoids act as? What are they involved in?
paracrines and neurotransmitters
they are hydrophobic
involved in inflammation and pain
ex. prostaglandins, leuotrienes anandamide
What type of messenger do gases act as? What are some examples?
paracrines mostly
ex. Nitric Oxide (NO), carbon monoxide
What type of messenger do purines act as? what are some examples?
neuromodulators, neurotransmitters, paracrines
ex. adenosine, AMP, ATP, GTP
T or F: ligand-receptor interactions are not very specific
false, they are very specific
What are the 2 types of actions that a chemical can have when a ligand binds to a receptor?
antagonistic
agonistic
Describe antagonists - what is the effect of these ligands?
chemicals that bind to receptors but don’t activate them
they inhibit other ligands that are meant to bind to the receptor from binding so they inhibit the response
describe agonists - what is the effect of the ligands?
chemicals that bind to and activate receptors
they stimulate a response
Are agonists and antagonists the natural ligands that bind to/match receptors? explain
no they mimic the natural ligand and either stimulate or prevent a response
T or F: receptor type determines the cellular response - explain
true
a target cell is only able to respond to a ligand if the right receptor exists on/in the target cell
T or F: there can be hundreds of chemical messengers and a given cell responds to all of them
false, a given cell can only respond to some of the hundreds of chemical messenger and which ones depend on the receptors present on/in the target cell
How are cells able to respond to specific and different combinations of chemical messages?
cells have a specific and variable combination of receptors so the chemical messages they can respond to depend on the type and combinations of those receptors
T or F: receptors have multiple domains
true - the binding site is located in the ligand-binding domain and other functional domains for signal transduction
What determines the type of ligands that can bind to the receptor?
the structure of the ligand-binding domain on the receptor
What determines the effects of the receptor on the target cell?
the other functional domains of the receptor
T or F: a ligand can bind to more than one receptor
true
T or F: the number of ligand bound to receptors on a cell can increase indefinitely
false, there is a saturation point at which no more ligands can bind to the receptors
Describe the relationship between ligand concentration and receptors on a cell
as the concentration of ligands increases, more ligands are able to bind to the receptors
this increases the response in a cell but eventually the receptors will reach a saturation point
at which no more ligands can bind and no addition of ligands will increase cellular response
How does the concentration of receptors on a target cell affect the cell responses?
higher concentrations of receptors will increase the chances of ligands binding to the receptors (regardless of the ligand concentration) and increase cellular response
T or F: the number of receptors on a target cell are constant over time
false, they can change
Give an example of how target cells can have a variable amount of receptors over time for down-regulation
if a person consumes heroin on a regular basis, the number of opiate receptors on the target cells decrease = reduces the cell response (pleasure) - ie., the person builds a ‘tolerance’ to the drug and requires a higher dose to achieve the same effects
if the person stops taking heroin, the low level of opiate receptors means the natural ligand, endorphin, has less ability to bind = withdrawal symptoms
eventually, the natural receptor numbers will return to normal and withdrawal symptoms will stop
Give an example of how target cells can have a variable amount of receptors over time for up-regulation
caffeine binds to receptors (in place of the natural ligand, adenosine)
adenosine is a neurotransmitter that binds to receptors and causes inhibition of brain activity = calming response
when caffeine binds to the receptors but doesn’t activate them (antagonistic) caffeine acts as a stimulant because it prevents the calming effects of adenosine
this causes the increase of adenosine receptors = up-regulated
a tolerance can be built and a consumer will require more caffeine to achieve the same effect
if a habitual coffee drinker stops drinking coffee, the high level of adenosine receptors in the brain will bind more with adenosine and have a sleepy effect on the person
What is the dissociation constant?
the strength of which a ligand binds to a receptor
Kd = the concentration of the messenger when half the cell’s receptors are bound to a ligand
If receptors have high affinity (strong binding), will they have a high or low dissociation constant?
low because the bonds between receptors and ligands are strong and therefore dissociation is less likely
If receptors have low affinity (weak binding), will they have a high or low dissociation constant?
high because the bonds are weak between receptors and ligands so dissociation is more likely
if the affinity constant (Ka) is larger, the ligand has a stronger or weaker bond to the receptor?
stronger
T or F: a high-affinity receptor will have a larger response in a target cell at low ligand concentration than a low-affinity receptor
true
What happens when a ligand binds to a receptor?
a conformational change occurs to the receptor which activates a signal transduction pathway to use the change in the shape of a receptor to cause a response within the cell
What is the function of signal transduction pathways?
they convert the conformational change that occurs to a receptor when the ligand binds to it and cause a response within the cell
What are the 4 components of signal transducers?
receiver
transducer
amplifier
responder
What is the function of the receiver? what has that role?
the ligand-binding domain of the receptor is the receiver
when it receives the signal it binds to that chemical messenger that’s coming in
What is the function of the transducer? what has that role?
the ligand-binding domain + other domains of the receptor function as the transducer
the transducer undergoes the conformational change and causes the activation of the signal transduction pathway
What is the function of the amplifier? what has that role?
the entire signal transduction pathway is the amplifier and functions to increase the amount of molecules that the signal affects
What is the function of the responder? what has that role?
changes to a variety (and one or more) molecular functions in response to a signal
ex. gene expression, protein activity, cell membrane permeability
T or F: all signal transduction pathways have different structures
false, they all have a similar general structure
Describe the general structure of signal transduction pathways
- ligand binds to receptor = conformational change to the receptor
- conformational change to the receptor is a signal that activates an inactive substance
- activated substance then activates a second substance
- the second activated substance then activates a third
this cascade continues until the last substance us activated
Describe how a longer signal transduction cascade can cause higher signal amplification
multiple molecules of a substance can be activated by the conformational change in a single receptor caused by the binding of a single ligand = that activated substance can then activate multiple molecules of the second substance and so on
What are the 4 types of receptors involved in the 4 common signal transduction pathways?
intracellular receptors
ligand-gated ion channels
receptor-enzymes
G protein-coupled receptors
Briefly describe the signal transduction pathway that involves intracellular receptors
these receptors are within a cell and interact only with hydrophobic chemical messengers
- hydrophobic ligand passes through membrane to intracellular space
- ligand binds to intracellular receptor at the ligand-binding domain
- receptor changes shape and is activated
- receptor-ligand complex moves to the nucleus
- the DNA-binding domain binds to DNA sequences
- increases or decreases production of specific mRNA
this signal pathway is involved in gene transcription
Briefly describe the signal transduction pathway that involves ligand-gated ion channels
these receptors change the ion permeability of the membrane causing a response in the target cell
hydrophilic, extracellular ligands bind to a transmembrane receptor on the cell surface
- ligand binds to a ligand-gated ion channel
- conformational change of the ligand-gated ion channel and opens the ion channel
- ions can now move into or out of the cell (depending on their electrochemical gradient) = effects the membrane potential
- change to membrane potential is a signal within the cell - this can be rapid
- amplification can occur
Briefly describe the signal transduction pathway that involves receptor-enzymes
these receptors activate or inactivate intracellular enzymes to cause a response in the target cell
hydrophilic, extracellular ligands bind to a transmembrane receptor on the cell surface
they have 3 domains: extracellular ligand-binding, transmembrane domain, intracellular catalytic domain
- ligand binds to ligand-binding domain
- receptor changes shape
- transmembrane domain transfers the shape change across the membrane
- catalytic domain is activated
- activates phosphorylation cascades
- response in the target cell
How does the intracellular signaling pathway effect gene transcription?
the binding of a ligand to an intracellular receptor causes a cascade of effects within the cell
generally:
- activation of small number of specific genes that usually code for other transcription factors
- gene products activate other genes which activate other genes and so on
basically, it’s just amplification but these can have effects on many biochemical pathways
What are some examples of ligand-gated ion channels?
Glutamate receptors (AMPA, NMDA, kainate)
GABAA receptors
nicotinic acetylcholine receptors
5-HT3, P2X
T or F: receptor-enzymes are enzymes
false, they are named so because of the reaction catalyzed by their intracellular catalytic domain
What are the 3 classes of receptor-enzymes? which are the most common in animals?
receptor guanylate cyclases
receptor tyrosine kinases - most common
receptor serine/threonine kinases
What are the receptor tyrosine kinases signals important for?
cellular growth/proliferation
Describe the steps of the receptor tyrosine kinases signal
- ligand binds to receptor tyrosine kinase
- dimerization of RTKs (bound receptor associates with another RTK)
- transautophosphorylation (RTKs phosphorylate each other on multiple tyrosine residues)
- activated/phosphorylated receptors active other (protein kinases) intracellular signaling molecules
- activated protein kinases signal to Ras protein
- Ras protein binds to and hydrolyzes GTP
Ras can be in an active state, when GTP is bound, or an inactive state when GDP is bound
- Ras activates serine/threonine phosphorylation cascades to signal through the cell
How do receptor tyrosine kinases regulate the activity of Ras proteins?
by signaling through GAPs and GNRPs
GTPase-activating proteins (GAP) catalyze the inactivation of Ras (GTP -> GDP-bound)
Guanine nucleotide-releasing proteins (GNRPs, or Guanine exchange factors GEFs) catalyze the activation of Ras (GDP -> GTP)
What is the function of Ras proteins in the receptor tyrosine kinase signal pathway? what’s one major effect?
Activated Ras activates a serine/threonine phosphorylation cascade which can have many effects
ex. signaling of Mitogen activated protein kinases (MAP kinases)
What happens when Ras proteins cause the phosphorylation cascade which causes the signaling of MAP kinases?
- Activated Ras signals to MAPKKK
- MAPKKK phosphorylates a MAPKK
- MAPKK phosphorylates a MAPK
- MAPK phosphorylates other kinases, cellular proteins, and transcription factors
T or F: Ras proteins have a wide variety of effects on cellular growth and metabolism
true, they massively amplify the signal triggered by RTKs
What’s a consequence of the signal cascade and amplification caused by Ras?
~30% of human cancers involve mutations in genes that code for Ras in which Ras is continuously activated even when there’s no ligand bound to RTKs = uncontrollable cell growth and division
Explain how the insulin receptor is another critical RTK?
- insulin (ligand) binds to the RTK causing dimerization
- transautophosphorylation of RTKs
- intracellular domains phosphorylate other proteins including the insulin receptor substrate (IRS)
- IRS acts as a docking site for other signaling proteins to be activated
Describe the steps of the receptor guanylate cyclases enzyme receptor
- receptor binds to receptor GC
- conformational change of RGC, activating the GC domain
- activated GC releases cyclic GMP
- cGMP acts as a 2nd messenger intracellularly to activate protein kinase G (PKG)
- PKG phosphorylates proteins at serine or threonine residues
- phosphorylated proteins activate other proteins causing a signal cascade
What is an example of a receptor guanlyl cyclase pathway?
atrial natriuretic peptide: regulates extracellular fluid volume (ECF) and blood pressure
peptide is released from the atrium of the heart when there’s a signal that there’s a high veinous return of blood into the heart
the peptide stretches blood vessels (vasodilation) to lower blood pressure and relax smooth muscles
Briefly describe the signal transduction pathway that involves G protein-coupled receptors
a signal transduction pathway causes a response in the target cell when the receptor communicates a signal to a G protein
hydrophilic, extracellular ligands bind to a transmembrane receptor on the cell surface
1.
Describe G-protein-coupled receptors
7 transmembrane domains
G-protein = ability of receptor to bind Guanosine nucleotides
What type of G proteins do G protein receptors bind to?
heterotrimeric G proteins that hydrolyze GTP
contain:
alpha - binding site for guanosine nucleotides are located on this subunit
beta and gamma are tightly bound to each other subunits
T or F: only the activated Ga subunit has downstream effects
false, the beta/gamma subunit can also have effects
What are the 3 major types of G protein-coupled receptors?
G-alpha s
G-alpha i (or o)
G-alpha q
What does Galphas do? give examples of these receptors
STIMULATES adenylate cyclase, cAMP and PKA
ex. Beta-adrenergic receptors, glucagon receptors, stimulates Ca2+ channels, inhibits K+ channels, D1 dopamine receptors
What does Galphai/o do? give examples of these receptors
INHIBITS adenylate cyclase, cAMP, and PKA
ex. glucagon receptors, inhibits Ca2+ channels, M4 muscarinic receptors, alpha2-adrenergic receptors, stimulates GIRK channels, D2 dopamine receptors
What does Galphaq do? give examples of these receptors
Activates PLC-beta
ex. alpha1-adrenergic receptors, M1 muscarinic acetylocholine receptors
What are 4 major secondary messengers in signaling pathways?
calcium (Ca2+) > binds to calmodulin to influence enzyme activity
cGMP > activates protein kinase G to phosphorylate proteins + regulate ion channels
cAMP > activates protein kinase A to phosphorylate proteins + regulate ion channels
phosphatidyl inositol > activates protein kinase C and causes Ca2+ release from intracellular storage (in endoplasmic reticulum) to phosphorylate proteins + influence enzyme activity
Describe inositol-phospholipid signaling
A Gaq regulated G protein-coupled receptor pathway
- ligand binds to GCPR = conformational change
- Gaq subunit releases GDP to bind to GTP
- activated Gaq activates phospholipase C
- phospholipase C cleaves PIP2 = IP3 + DAG
- in the membrane, DAG forms arachidonic acid to synthesize eicosanoids (chemical messengers)
- IP3 is released into cytoplasm
- IP3 either is phosphorylated or binds to Ca2+ channels to release endoplasmic reticulum stores of Ca2+
- Ca2+ binds to calmodulin = variety of effects
- Ca2+ also pushes protein kinase C (PKC) to the membrane
- DAG activates PKC in the membrane causing a phosphorylation cascade
Describe adenlyate cyclase signaling
a Gas and Gai regulated G protein-coupled receptor pathway
- ligand binds to GCPR = conformational change
- Gas subunit releases GDP to bind to GTP and activates adenylate cyclase
- activated adenylate cyclase catalyzes ATP > cAMP (cyclic)
- cAMP binds to regulatory subunit of PKA = dissociates from the catalytic subunit of PKA = activated PKA
- activated PKA subunit phosphorylates proteins causing a response
- serine/threonine phosphatases quickly dephosphorylate the activated proteins to stop the response
- ligand binds to the Gai CPR, the ai subunit inhibits adenylate cycle and stops the transduction pathway
How is the adenylate cyclase signal pathway inhibited?
when a ligand binds to the Gai protein-coupled receptor, the ai subunit inhibits adenylate cyclase and prevents the signal pathway from continuing
or
serine/threonine phosphatases will dephosphorylate proteins that have been phosphorylated by the catalytic domain of PKA and terminate the response
