Module 4 Flashcards
cell-to-cell communication
allow cells to communicate to perform tasks
-achieved by release of substances from cell that travel to another cell and cause it to change its function
concept of intracellular transduction
-cell detects single
-single relayed into cell-
-cascade of events
-response single created
Extracellular verse intracellular communication
extracellular
-single from outside of cell recieved
-can occur at multiple distances and multiple strategies to do this
intracellular
-external single causes a change within cell
-collect info, sythesize info, make decisions on how to respond to information
How extracellular singles relayed
Direct-cell-to-cell communication
Gap junctions
-made of connexions which hydrophilic channel which dock together to form channels between cells
-allow chemical signals to directly move between cells
-highly regulated and can open and close as appropriate
-only small particles pass through (not proteins, carbohydrates, larger molecules) and electrical signals heading to cardiovascular cells
-gating system self-defense mechanism so can protect from neighbouring dangers
-the 2 halfs attach across intercellular gaps
-important in cardiac muscle contraction
cell-to-cell communication
~cells who dont touch. each differenciate based on type of cell/location signal arrives
Autocrine Secretion
-substance released by cell and effect same cell
Paracrine secretion
-substance released by cell and effect nearby cell
Endocrine Secretion
-substances released by cell and have effect on distant cell
ALL BUT NEUROTRANSMITTERS CASUALLY DIFFUSE THROUGH THE BLOODSTREAM OR EXTRACELLULAR AREA TO REACH RECEPTOR
Neurotransmitters
-substances released by nerve terminal into synapse for short period of time
-occur when nerve cell axon terminates onto target cell
-1. excitatory single comes down axon to synapse
-2. neurotrasmitters are released into synapse where bind to receptor on target cell or degraded by enzymes in synapse, or taken back up by nerve cell
-
How intracellular communication relayed
Purpose to convert extracellular information to appropriate cellular response through process of signal trasnduction:
-external stimuli like secretion interacts with a receptor on Plasma membrane
-triggers effect within cell and process what signal means
-once know what signal is, cell produces response through effector
Components of signal transduction
The Signal
-either membrane permeable or membrane impermeable
The receptors
-the receptors interact with the signal
The Signalling Proteins
-proteins which help conduct the signal intracellularly
Second messengers
-non-protein molecules that help conduct signal intracellulary
Structure of signalling pathway
Membrane-permeable signal molecules
-bind to receptor proteins in the cytosol
membrane-impermeable signal molecules
-bind to transmembrane cell surface receptor proteins which then activate second messengers
signalling proteins and second messengers
-amplify, process and distribute incoming signals from both classes of signal receptor proteins
cytoplasmic effectors
-some signals sent to effector proteins in cytosol. quick and short-lived response to signalling pathway
Nuclear effectors
-some signals terminate at effectors in nucleus
-these effectors are transcription factors that control gene expression
-result in slower more prolonged response to signalling pathway
List quick overview of 5 parts of signal transduction
- signals
- receptors
- signalling proteins
- second messengers
- effectors
Signal transduction pathways
Linear
-one receptor interacts with one signalling protein or second messenger and one effector
covergent
-several receptors share common signalling proteins or second messengers an can all lead to one effector
divergent
-a signal receptor can interact with multiple signalling proteins or second messengers
Multi-branched
combination of divergence and covergence all happening at same time
Transduction:Signal
-aka ligands
-arise from extracellular space and bind to receptor
-signal-triggering molecule that binds on site of target protein
Membrane-impermeable
-majority
-cannot penetrate through membrane
-bind to surface receptors and grouped into 5 classes based off structure, binding partners and cellular location
Membrane-permeable
-mainly steroids
-penetrate through membrane
-not limited to membrane receptors but can interact with cytosolic receptors
Physical Signals
-include temperature, light, pressure
Transduction:Receptors
-the lock
-often found on plasma membrane but can be located inside cytoplasm (nuclear receptor only)
-6 classes
G-Protein Coupled Receptors
- superfamily receptors with hundreds of genes coding for different receptors
-physiological reactions including detect smell
-activate flight or fight response
-7 domains (H1-H7)
-heterotrimeric G-Protein 3 subunits (alpha, beta, gamma) who interact with eachother
-function: binding ligand cause conformational shape change (GDP to GTP)
-leads to activation of coupled G-protein subunits
Ion channel receptor
-aka ligand-gated channel receptor
-exist in plasma membrane
-permit ion flow from one side of membrane to another
-when specific ligand binds-> confirmational change occur that open pores to allow ion through
-NOT ENZYMES
ex. responsible for voluntaryv muscle contractions and common for much communciation between nerve cells through release of neurotransmitters like acetylcholine
Guanylate Cyclase
-aka guanylyl cylclase
-found in both membrane and soluble within cytosol
-membrane bound (one focus on)- contains externalized ligand binding domain, a transmembrane, and internal cataytic domain
-cytosol bound- act as target in addition to mediating intracellular process
-membrane:
-when activated, guanylate catalytic domain converts GTP into cGMP.
-cGMP binds to other singalling protien and initate celllular processes
-plas role in vision as convert light signal to electrical signal for eye
Protein Kinase
–hundred different
-not all surface receptors, many cytosolic proteins that help signal transduction, alter enzyme activity, or other cellular processes
-generally, phosphorylate other proteins that contain serine, threonine, or tyrosine residues
-dysfunction involved with cancer types
2 classes:
1. receptor tyrsosine kinase (RTK) (phosphorylate tyrosine)
2. sernine/threonine kinase receptor (S/TKR) (phosphorylate sernine/threonine)
Binding of protein tyrosine kinase receptor
inactive-
before binding receptors inactive adn seperate polypeptides with inactive tyrosine kinase domains
Dimerization
-signal molecule binds -> two subunit receptors join (dimerize) forming a dimer. now kinase active
Transautophosphorylation
-cytoplasmic tail of one subunit brought close to tyrosine kinase domain of another and opposite domain is phosphorylated on tyrosine amino acids
Binding sites
-resulting phosphotyrosine amino acids binding sites for additional signalling proteins who pass
resetting
Transmembrane scaffolds
-no distinct function
-form in large structures of receptors and signaling proteins with complex interactions, regulating signal transduction
-determine which proteins can bind to complex
-associate with membrane receptor
-form what is called a signalling scaffold
-isolate signalling pathways
-bring signalling proteins together
-localize singalling proteins to specific area
Nuclear receptors
-aka transcription factors as regulate gene
-found in cytosol of cells
-ex. with steroids
-once bound receptors move through nuclear pore compelxes directly into nucelus
-once inside nucelus, activated receptor complex bind to specific DNA sequence called SRE (steroid response elements) and by this mechanism control expression of genes
-also play role in response to toxic substances like constituents in tobacco smoke
Transduction: Signalling Proteins
-6 classes
-key
2 common features
1. mobility-highly mobile, diffuse rapidly through cytosol/ move rapidly in membrane if applicable
2. cataysis-either catalyze chemical reactions for signal amplification or capable of binding to ezymes
-main role-transmit and amplify signals
-can mobilize second messengers (non-protein molecules who link signalling proteins together into further signalling proteins or other direct actions)
G-Proteins
-bind to GTP and propagate signals
2 families which differ in number of polypeptides which made from
1. Monomeric G-Proteins
-single polypeptides which contain 2 different binding sites (1 for GTP or GDP and 1 for target protein) and a GTPase domain
-when GTP bound, in activation state and can bind to target protein
-GTPase cleave the GTP to form GDP
-GDP released
-GTP bind again to reactivate
*Not GPCRs
2. Heterotrimeric G-Proteins
-3 different polypeptides
-G-proteins anchored to plasma membrane and activated by G-protein coupled receptors
-alpha subunit analogous to monomeric G-protein which binds to GTP/GDP and target protein. beta/gamma subunits attached together stabilize inactive (GDP) bound alpha subunit
4 steps in G-Protein activiation
1. binding
-heterotrimer containing alpha and beta/gamma subunit bound to GDP (inactive form)
-when ligand binds to receptor, changes confirmation to interact with heterotrimeric G-protein
2. seperation
-receptor cause exchange of GDP with GTP on aplha
-heterotrimer seperates alpha and beta/gamma subunits
-G-proteins active
3. Propagate
-alpha ( interact with one effector like adenylate cyclase) and beta/gamma subunits ( interact another effector) separately bind downstream targets, propagating the signal pathway
4. Cleave and reform
-alpha subunit cleaves GTP to form GDP
-alpha and beta/gamma subunits reform heterotrimer
-returns heterotrimeric G-Protein complex to inactive form
Protein Kinase
-enzymes who attach phosphate groups to tyrosine, serine, and theronine amino acids
-majority of kinases are cytosolic kinase
-act as intermediaries activate other kinase/ signalling proteins once active
-phosphorylate effector (ATP-ADP)
-enter nucleus and phosphorylate proteins which directly interact with DNA
-phosphorylating target proteins mostly activates them but sometimes turns some off.
Calcium-binding proteins
-Typically Ca2+ kept low intracellular concentrations so when levels increase from signalling event, it can interact with certain proteins causing downstream effects
-ex. calmodulin that binds with Ca2+ with high levels and induces a confirmational change that allows calmodulin to bind to target protein (wrap around it)
-some act as signalling molecules, other enzymes depending on location
Adenylyl cyclase
-aka adenylate cyclase
-related to guanylyl cylcase as nucelotide triphosphate converted into another form
-ATP -> cAMP, causing singal
-not linked to membrane receptors, it binds to alpha subunit of heterotrimeric G-Proteins (explain why singalling)
*NOTE_ phosphodiesterase converts cAMP to AMP by cleaving phosphodiester bond between phosphate and 3’ carbon of ribose
Adenylyl Cyclase subunits
-2 types of heterotrimeric G protein alpha subunits: as stimulates adenylyl cyclase while ai inhibits it
-different types form parts of different heterotrimeric G-Proteins and linked to different GPCRs which highlight level of cellular decision making in which multiple pathways converge to get signal response
Lipid Kinase
-phosphorylate phospholipids head group in cytoplasmic leaflet membrane
-cause conformational change in phospholipid and it can now bind to to target protein in membrane to pass single down pathways
* some phosphorylated more than once before activated with signal
Adaptor proteins
-nearly all signal transduction pathway have
-neither receptor or enzyme
-different binding domains which recongize phosphorylated amino acids or other activated structures on signalling proteins
-domains glue/ hold elements/cascades together at right time and place to complete tasks
ex. tyrosine of FGF-receptor phosphorylated, adaptor protein Grb2 binds and undergo conformational change that allow bind to Sos. BRb2 hold these elements.
Transduction: Second Messengers
-non-protein ions and molecules
ex. cAMP and calcium ions
-rely signaling information from signalling proteins to other cellular targets (first messengers ligands that interact with receptor)
-smalll in size
-diffuse rapidly in cytosol or membrane
-amplify signals so that the interaction of just a few ligands with receptors cause larger response within cell by mobilizing second messengers
-not hang in cytosol for long
-cAMP and cGMP degrated by specific enzymes called phosphodiesterases, which ionic messengers like Ca2+ sequestered into cellular organelles
other ex. small hydrophobic molecules like DAG, IP3, NO
Specific pathway examples of the heterotrimeric G-Protein signalling cascade (dont hang up on details)
GPCRS
-over 800 who respond to wide variety stimuli like chemical modulators (neurotrandmitters, hormones, odourants) and physical stimuli (light)
-pathway initiated by binding of ligand to GPCR.
-binding of receptor allow receptor protein to interact with heterotrimeric G-Protein
cAMP
-stimulates replacement of GDP for GTP in Ga subunit
-causes hterorimeric G-protein to dissociate from receptor and leave G (beta/gamma) subunits and an activated Gas-GTP
in that ex. Gas-GTP bind to actiavates signalling protein adenylyl cyclase to convert ATP into cAMP
PKA
-cAMP bind to protein kinase
-inactive PKA a tetrameric protein with 2 regulatory subunits and catalytic subunits
-binding cAMP on regulatory subunits cause protein dissociate and release active cataylic subunit
-once activated cataylic subunit can phosphorylate a number of cellular processes
CREB
-active PKA cataylic domains enter nucleus
-common nuclear target is CREB
-once phsophorylated by PKA, CREb binds CBP and together, two proteins interact with DNA to initate transcription
Specific pathway examples of the phospholipid kinase signalling cascade (dont hang up on details)
GPCR
-signal transduction pathway initated by binding of ligand to GPCR
-binding of receptor allows receptor protein to interact with heterotrimeric G-Protein
-ligand bound receptor stimulates replacement of GDP to GTP in Ga subunit
-causes hterotrimeric G-protein to dissociate from receptor and itself to leave a G(beta/gamma) subunit and an activated Ga-GTP
PLC
-Ga-GTP binds the PLC
PIP2/IP3
-activated PLC breaks down PIP2 to release two second messengers, DAG and IP3
Ca2+
-IP3 difusses freely in cytosol and activates its receptor on endoplasmic reticulum which opens a ligand-gated calcium channel
-ca2+ leaves endoplasmic reticulum and acting as second messenger can activate a number of calcium binding proteins
PKC
-Together membrane bound diacylgycerol and cytosolic Ca2+ bind to protein PKC resulting in its activation
-Activated PKC has numerous cellular targets that can phsophorylate to modulate the target’s activity
Specific pathway examples of the protein kinase signalling cascade (don’t hang up on details)
FGFs
-fibroblast growth factors
-stimulate growth of most mammalian cells
-bind to FGFRS (homodimeric (2 identical protein subunits) receptor kinase (tyrosine kinase))
-binding of FGF to FGFR causes subunits to dimerize
-once bounded FGFR undergo tyrosine transutophosphorylation to form phosphotyrosines on cyotplasmic side.
-phosphotyrosines can be bound by a multitude of different proteins
Grb2
-adaptor protein
-binding to phsophotyrosine caused Grb2 to undergo conformational change to bind Sos
-binding Sos to Ras replaces GDP to GTP and now active Ras can bind to serine/theronine kinase called Raf
-activated Raf can phophorylate MEK which will phsophorylate Erk
-form dimer and can phsophorylate other signalling proteins in either cytosol or nucelus
in this ex. Erk enters nucelus to activate transcription factors, initiating transcription
in liver another example
What three things break down waste
Lysosomes
-organelles that break down miss-folded and damaged organelles, nucleic acids, lipids, and more and proteins which not endogenous to cell or from other organelles
-enzymes like protease who cleave membrane prooteins and proteins in lysosome
-enzymes that cleave and digest fats, sugar
-large molecules broken down (ex. amino acids) can be transported to cytosol so cell can reuse
Proteasomes
-protein complexes that specifically break down damaged and misfolded proteins in nucelus and cytosol
Peroxisomes
-hazardous
-handle adn spot to safely use these dangerous free radicals including reactive oxygen species (ex. catalase)
-problematic to cell
-need safe space to use those chemicals
-small membrane bound organelles
-contain enzyme which calayses various metabolic reactions
-essentail peroxisome proteins called peroxins; synthesized in cytosol and targeted to peroxisome by specific peroxisomal targeting signals (PTSs)
-also decompose for cargo like uric acid, amino acids, long fatty acids chains
Getting cargo into lysosome
-content tagged for lysosome by M6P
-cargo delievered in endsome via endomembrane system
-protease which enzyme who degrade damaged proteins also directed to lysosome with same m6P tag
Vesicles
-engulfed proteins delivered by vesicles that empty their content by fusing with lyssosome and are digested by proteases
Proteases
-synthesized in ER, tagged with M6P and delivered to lysosome by vesicles
-digest both souble and memrbane proteins in lysosome
Protein degration by proteasome
-degrades intracellular proteins in cytosol and nucelus
-require process of ubiquitination ( form of post-translational modifications of proteins)
Cytosolic degration by proteasome
-missfolded or damaged tagged with polyubiquitin chain (composed of multiple molecules of ubiquintin)
-multiple ubiquintin required to be targetted and recongized
Nuclear Proteins
-in nucelus, degrade unwanted proteins then and there
-ex. damaged histones
Cell dealth
Apoptosis
-programmed cell death
-energy consuming process
-cleanly and carefully ends cell life
-protects body from damaged cells that no longer properly function
-used in development ex. removing webbing between toes
Necrosis
-normally result of cellular injury
-cell attempts to repair self
-stressed cells may show swelling in mitochondria and endoplasmic reticulum or some blebbing but return to normal if recover
-major pathway pf cell death as result of sever damage that not able to be repaired
-cell’s organelles not able to function and it dies
Mechanism of apoptosis
- Initiation
-2 different pathways
Intrinsic: cell initates apoptosis itselfs
-originates in outer membrane of mitochondria
-intracellular signals like severe DNA damage, ROS, toxins, trauma turn on this pathway
External: external signal initates apoptosis
-uses plasma membrane receptor called death receptor
-neighbouring cells like immune cells release death ligands which bind to death receptors on damaged cells
-leads to apoptosis - membrane blebbing and enzyme activiation
-cell starts shrinking and forming blebs (first visible sight undergoing apoptosis)
-enzymes termed caspases activated
-initator caspases activated by enternal or instrinic pathway
-caspases cleave and thereforre activate other caspases known as executioner caspases - Cell structure changes
-after executioner activated,
-dna fragmented often between histones and DNA repair halts
-nucelar membrane breaks down and nucelus diasppears
-cytoskeleton dissassembled and plasma mebrane phospholipid content changes with scramblases, with PS being exposed on exoplasmic leaflet of plasma membrane
-organelles persist and enclosed in apoptotic bodies - Engluflment
-Phagocytes endocytose the apoptoic bodies to dispose of them
-these then safelty digested by phagocytes’ lysosomes
-causes minimal amount of disturbance to cells and surrounding tissues
what is blebs
small protrusions from the plasma membrane
what is phagocytes
immune cells that engluf foreign bodies
Mechanism of necorsis
- Damage
-cell damaged beyond repair from toxins, extreme heat or radiation, freezing, ischemia, pathogens, mechanical trauma - Swelling
-organelle lose structure and begins to swell
-vacuoles or undefined bodies form in cel
-depending on cell type, DNA may be degraded - Destruction
-membrane and remaining organelles lose structural integrity
-holes observed under microscope
-cellular content spills out of cell, producing inflammatory signalas
-mitochondria’s proteins released
-lysosomal contents are exposed
-cells nearby exposed to remains of cell and are also damaged or have apoptosis signalling triggered
-difficult for body to clean up the cellular remains after necrosis
