Lecture 6- Biochemistry of signaling pathways Flashcards
minus gap junction signaling, what does cell to cell signaling require? (3)
signal (ligand)
receptor
way to get the message across (intracellular signaling pathways)
what is a signal transduction pathway?
information from secreted signals is converted to intracellular signal pathways, therefore, converts one form of signal to another
explain signal transduction (5)
signal molecule –> binds to receptor protein –> activates intracellular signal molecules –> causes alterations of target proteins –> creates a biological response
are signal pathways ubiquitous/ everywhere?
all cells have some pathways and only certain cells have specific pathways
why are signal pathways important?
they amplify signals to cause a large biological effect
what are the two main categories based on receptor location?
intracellular receptors
cell membrane receptors
what state are ligands in with intracellular receptors?
lipophilic (hydrophobic), therefore fat soluble
with intracellular receptors can ligands diffuse through cell membrane? what do they bind to?
yes, then they bind to receptors in the nucleus or cytosol
what do intracellular receptors alter?
gene expression (happens slowly but its long lasting)
with intracellular signal receptors is the response fast?
no, theyre slower responses that are related to changes in gene activity
what state are ligands in with cell membrane receptors?
lipophobic (hydrophilic) water soluble
with cell membrane receptors can ligands diffuse through cell membrane? what do they bind to?
no, they bind to membrane receptors which cause intracellular cascade
with cell membrane receptors is the response fast?
yes
what are the 4 cell membrane receptors?
integrin receptor
receptor channel
receptor- enzyme
G protein- coupled receptor
what does the integrin receptor do?
binds extracellular matrix proteins
binding of the ligand with integrin receptor stimulates what change?
changes in the cytoskeleton
what can changes in the cytoskeleton affect?
cell movement
growth
wound healing
how do receptor channels work?
ligand binds to the receptor channel protein and a channel gate either opens or closes (allowing ions to ener and leave).
this alters the cells permeability to an ion and membrane potential
how do receptor channels have an electrical effect?
when activated ions cross cell membrane they are charged which causes an electrical signal/ effect
what ligand normally binds to a receptor channel?
neurotransmitter
what ion is always allowed into cells through receptor channels?
Calcium!!! (important for intracellular signal)
recall: Ca++ inside the cell is low
what are receptor channels often called?
ligand- gated ion channels
neurotransmitter gated ion channels
ionotropic receptors
what do receptor enzymes and GPCR have in common?
activate amplifier enzymes
how does signal amplification work?
receptor- ligand complex activates an amplifier enzyme
1 ligand is amplified into many intracellular molecules
what is the takeaway message about the ligand from signal amplification?
a small amount of ligand creates a large effect
what is an example of a receptor enzyme pathway?
tyrosine kinase receptor
what is the general goal of tyrosine kinase receptors?
to transfer a phosphate group from ATP to a tyrosine residue (amino acid) of a protein which phosphorylates tyrosine residues
what is a specific example of tyrosine kinase receptor?
insulin receptor
what does a complete insulin receptor contain?
alpha receptor (contains ligand binding domain)
beta subunit (is transmembrane and contains the signaling domain
how does the insulin receptor work in tyrosine kinase receptor? (7)
- insulin binds to alpha subunit of receptor
- causes activation in beta subunit of the receptor 3. which causes them to dimerize (combine 2 identical units together) and automatically phosphorylate (auto phosphorylate themselves)
- beta subunit send the signal of the insulin to the cytoplasm
- kinase domain in the cytoplasm is activated
- kinase domains on the receptor phosphorylate insulin receptor substrate
- other responses in the cell are triggered
what are orphan receptors?
there are hundreds of known GPCR but many have unknown function
what are GPCRs also called?
metabotropic receptors
7 transmembrane domain receptor
serpentine receptor
why might GPCRs be called 7 transmembrane domain receptor?
they have 7 transmembrane proteins
what does teh activation of GPCR do?
leads to generation/ release of second messengers
what are second messengers?
signaling molecule synthesized or released by a cell in response to an extracellular signaling molecule like a hormone
what are different paths of a second messenger?
synthesized
released from a storage compartment
what form are second messengers in? hydrophobic, hydrophilic?
can be hydrophobic, hydrophilic or a gas
what does GPCR stand for?
G- protein coupled receptor
why are GPCRs called G- proteins?
because they bind GDP and GTP (guanosine diphosphate, guanosine triphosphate)
what is the inactive configuration of G- proteins?
bind GDP
what is the active configuration of G- proteins?
exchange GDP and GTP
what are 3 examples of GPCR?
adenylyl cyclase
phospholipase C
arachadonic acid
what is the process of Andenylyl cyclase?
1.ligand binds to G protein receptor
2. activates the G protein
3. once activated, the G- protein can diffuse along the inside leaf of the membrane
4. G- protein diffuses along the inside of the membrane 5. the amplifier enzyme Adenylyl Cyclase is now activated
6. Adenylyl cyclase converts hundreds of ATP into cAMP
7. cAMP activates protein kinase A (PKA)
8. PKA diffuses within cell to phosphorylate many other proteins
what can the activated receptor stimulate in Andenylyl cyclase?
several G- proteins
what does each G- protein activate in Andenylyl cyclase?
each G- protein activates one Andenylyl cyclase
what is cAMP in Adenylyl cyclase pathway?
second messenger
can diffuse throughout the cell
in Andenylyl cyclase does PKA only phosphorylate one type of protein?
no, many types of proteins can be phosphorylated, giving rise to complex cellular responses
what is the process of phospholipase C in GPCR?
- ligand binds to and activates G protein receptor
- G- protein activates the phospholipase- C (amplifier enzyme)
- PLC degrades membrane phospholipids (PIP2)
into TWO second messengers (diacylglycerol + inositol tri- phosphate), DAG in the membrane stays associated with phospholipid, IP3 is small and polar so it diffuses through the cytoplasm - DAG activates protein kinase C (PKC)
- PKC diffuses within the cell and phosphorylates other proteins
- IP3 binds to the IP3 receptor on the endoplasmic reticulum
- IP3 receptor is activated and allows stores of Ca++ to be released into the cytoplasm
what does Ca++ become in phospholipase C?
another second messanger
what are common second messengers?
cAMP
cGMP
IP3
DAG
Ca++
what are the 5 different things calcium can do as a second messenger?
Ca binds to the calcium- binding protein calmodulin to activate other proteins
Ca binds to motor proteins and allows action of cytoskeleton and motor proteins (muscle contraction)
Ca binds to synaptic proteins to trigger exocytosis
Ca binds to ion channels to modulate their gating (channels can be open all the time or gated (sometimes open, sometimes closed)
Ca in fertilized eggs initiates development
how are gases second messengers?
only soluble gasses are second messengers however they do bend the definition of second messenger
NO is an example of a soluble gas, what is unique about it?
has a life of 2- 30 seconds
explain the process of the gas nitric oxide (NO) in viagra cialis
- synthesized by endothelial cell of arteries or neurons of parasympathetic nervous system
- diffuse into adjacent arterial smooth muscle
- this activates guanylyl cyclase
- which produces cGMP
- which activates protein kinase G (PKG)
- which leads to relaxation of smooth muscle
what are two other molecules that do similar things to NO?
CO (carbon monoxide)
H2S (hydrogen sulfide)
what pathway is the arachidonic acid pathway similar to?
phospholipase C (PL-C pathway)
how does the arachidonic acid pathway work?
- G- proteins activate phospholipase A2 (amplifier enzyme)
- PLA2 degrades phospholipids into arachidonic acid
what are the two major groups of arachidonic acid- derived paracrine molecules to be aware of?
leukotrienes
prostaglandins thromboxanes (prostanoids)
what are leukotrienes, how did they come about?
arachidonic acid –> lipoxygenase –> leukotrienes
singulair tablets are a leukotriene receptor antagonist
what are prostaglandins, how did they come about?
arachidonic acid –> cycloxygenase –> prostaglandins thromboxanes
aspirin is an anti-inflammatory that binds to cycloxygenase
why does the hormone epinephrine (adrenaline) cause some blood vessels to constrict and others to dilate?
presence of receptor isoforms
what receptor isoform causes the blood vessel to constrict? on what type of blood vessel?
alpha receptor
intestinal blood vessel
what receptor isoform causes the blood vessel to dilate? on what type of blood vessel?
beta receptor
skeletal muscle blood vessel
what is the takeaway message about target response?
target response depends on the target receptor. thus the same hormone causes different effects of the hormone.
some ligands can activate multiple receptors
what does it mean that some receptors are promiscuous?
activated by more than one ligand
ex. alpha receptors may be activated by either epinephrine or norepinephrine. beta receptors may be activated by either epinephrine or norepinephrine
how many receptors might a cell contain?
hundreds or thousands of receptor proteins
what does it mean that the numbers of receptors can change over time?
need more receptors when developing at a young age
receptors can be desensitized, what does that mean?
receptors can become over stimulated
ex. people that overuse hard drugs, their tolerance wears off after a while because they over stimulated their receptors causing them to have desensitized receptors
what does the phosphorylation of alpha and beta receptors do?
causes them to have a lower affinity for ligands
