Module 4 Flashcards
how is cell communication achieved
release of substances from a cell that then travel to another cell and cause it to change its function
done though a signal that then must be relayed into the cell and trigger a cascade of events
cellular communication interrelation elements
- extracellular communication
- intracellular communication
what is extracellular communication
- communication that occurs when a signal is received from outside the cell itself
- communicate at variable distances and posses multiple strategies to communicate
what is intracellular communication
cells collect information from multiple sources, synthesize information then make decisions on how to respond to the information
what do cells in direct contact use to communicate
gap junctions
what do cells not touching use to communicate
four different types of secretion:
- autocrine secretion
- paracrine secretion
- endocrine secretion
- neurotransmitters
what are gap junctions made up of
connexons which dock together to form channels from one cell to another
allows chemical signals to move directly between cells
what can pass through gap junctions
only small particles such as ions and small signalling molecules can pass, larger molecules (proteins, carbohydrates) cant.
excitable cells (cardiac muscle cells) can pass electrical signals
gap junctions reglulation
dont allow free exchange of signals. highly regulated and open and close when appropriate (self defence mechanism from neighbouring cells)
autocrine secretion
(SAME) substances are released by a cell and have an effect on the same cell
paracrine secretion
(NEARBY) substances are released by a cell and have an effect on nearby cells
endocrine secretion
(DISTANT) substances are released by a cell and have an effect on distant cells
neurotransmitter secretion
substances are released by a nerve terminal into the synapse
autocrine, paracrine and endocrine secretion
all the same but vary in distance. substances diffuse through extracellular spaces or within the bloodstream to reach their target where they interact with a receptor to have an effect
how does neurotransmitter secretion occur
occur where a nerve cell axon terminates on a target cell
when an excitatory signal comes down the axon to the synapse neurotransmitters are released into the synapse
bind to a receptor on target cell, degrade by enzymes in the synapse or taken back up by nerve cells
what is required for secretion to have an effect
interaction with a receptor is required to initiate intracellular signalling cascades that produce specific responses
general process of intracellular communication
external stimuli (secretion) interacts with sensors on plasma membrane which triggers events within the cell (information processing), once the cell knows what the signal is produces a response to the signal through effector
what are the components of a signalling pathway (intracellular communication)
- signal (membrane permeable or impermeable)
- receptor (interact with signal)
- signalling proteins (help conduct signal intracellularly)
- second messengers (non protein molecules that help conduct signal intracellularly
process of the signalling pathway
- membrane permeable signal binds to receptor proteins in the cytosol / impermeable binds to transmembrane cell surface receptor proteins activates second messengers
- signalling proteins and second messengers amplify, process and distribute incoming signals from both classes of signal receptor proteins
- some signals sent to effector proteins in the cytosol (typically fast, short response to activation of pathway)
- some pathways terminate at effectors in the nucleus, effectors are transcription factors that control gene expression, slower more prolonged response
signal transduction pathway types
- linear
- convergent
- divergent
- multi branched
linear signal transduction pathway
one receptor interacts with one signalling protein or secondary messenger
convergent signal transduction pathway
several receptors share common signalling proteins or second messengers
divergent signal transduction pathway
single receptor interact with multiple signalling proteins or second messengers
multi branched signal transduction pathway
combination of convergence and divergence may be happening all at the same time
what are signals + types
also called ligands (signal trigger molecule)
arise from extracellular space and must bind to receptor to be effective
membrane impermeable - cant penetrate membrane and bind to cell surface receptors
membrane permeable (mainly steroids) not limited to membrane receptors and can penetrate membrane and interact with cytosolic receptors
physical signals - pressure, temperature and light
receptors types
- G protein coupled receptors (GPCR)
- ion channels
- guanylate cyclase
- protein kinase receptors
- transmembrane scaffolds
- nuclear receptors
G protein coupled receptors (GPCR) function + structure
superfamily of receptors, involved in many reactions (smell, flight or fight response)
combination of seven transmembrane domains (H1 to H7) and a heterotrimeric G protein with alpha, beta, gamma subunits that interact with eachother
binding of ligands cause conformation shape change leading to activation of coupled G protein subunit
ion channel receptors function
transmit signal information allowing ions to flow from one side of the membrane to the other
undergo conformational shift that opens pores and allows ions to flow through
unlike other receptors proteins these are not enzymes
common for communication between nerve cells through the release of neurotransmitters
responsible for voluntary muscle contraction
guanylate cyclase receptors structure + where its found
found both bound to membrane and soluble in cytosol
contain externalized ligand binding domain, transmembrane domain and internal catalytic domain
important for vision, convert light signal into electrical signal in eye
guanylate cyclase function
soluble form serves as a target for some membrane soluble ligands and mediates some intracellular processes
when activated catalytic domain converts GTP into cyclic guanosine monophosphate (cGMP) which binds to other signalling proteins to initiate cellular processes
protein kinase receptor function
note not all protein kinases are cell surface receptors
many are cytosolic proteins used in signal transduction, alter enzyme activity, etc
general action is to phosphorylate proteins with serine, threonine or tyrosine residues
types of protein kinase receptor
receptor tyrosine kinases (RTK)
serine/threonine kinases receptors (S/TRK)
process of protein tyrosine kinase receptor ligand binding
before ligand bind inactive receptors separate polypeptides with inactive tyrosine kinase domains
binding to signal cause two subunits of receptor to join (dimerize) forming a dimer (active now)
transautophosphorylation occurs when cytoplasmic tails of one subunit brought close to tyrosine kinase domain of other subunit and the opposite domain is phosphorylated on specific tyrosine amino acids
resulting phosphotyrsine amino acids are binding sites for more signalling proteins
ligand released, amino acids dephosphorylated by phosphoprotein phosphatase
kinase resets to inactive state
transmembrane scaffold receptors
do not always have a distinct function
tends to form in large clusters of receptors and signalling proteins
scaffold proteins determine which signalling proteins can bind to a complex
transmembrane scaffold receptors function
- bring signalling proteins togetehr
- regulate signal transduction
- localize signalling proteins to specific cellular areas
- isolate specific signalling pathways
nuclear receptors
found inside cytosol
once ligand binds receptros move through nuclear pore complexes directly to the nucleus
class of receptor also called transcription factors
also play an important role in response to toxic substances
nucelar receptor function
inside nucleus activated receptor binds to specific DNA sequence called steroid response elements (SREs) which controls expression of genes
signalling proteins features
mobility
- highly mobile, can diffuse rapidly through cytosol/plasma membrane (membrane associated)
catalysis
- catalyze chemical reactions for signal amplification
- capable of binding to enzymes
signalling proteins function
transmit and amplify signal information
also can mobilize second messengers (non protein) which link signalling proteins together, or have direct actions of their own
G protein (signalling protein)
bind GTP and propagate signals
two different families monomeric G proteins and heterotrimeric G proteins, differ in number of polypeptides
monomeric G proteins (signalling protein)
single polypeptides that contain two different binding sites (one for GTP/GDP and one for target protein) and a GTPase domain
not coupled to G protein coupled receptors
when GTP bound in activated state and can bind to target protein. GTPase then cleave GTP to form GDP which is eventually released so GTP can bind and reactivate
heterotrimeric G protein
contain three different polypeptides
anchored to plasma membrane
activated by G protein coupled receptors
alpha subunit binds GTP/GDP and target protein
beta/gamma subunits attached together and stabilize inactive form of the alpha subunit (GDP bound)
activity of G protein process
binding
- heterotrimer is bound to GDP (inactive)
- ligand binds the receptor changes conformation to interact with heterotrimeric G protein
seperation
- receptor causes exchange of GDP with GTP on alpha subunit
- heterotrimer separates into separate alpha and beta/gamma subunits (G protein active)
propagate
- while separated alpha and beta/gamma subunits bind downstream targets, propagating signal pathway
- subunits interact with different effectors
cleave and reform
- alpha subunits cleaves GTP to form GDP and subunits bind to reform heterotrimer
- returns to inactive form
protein kinases (signalling protein)
enzymes that attach phosphate groups to tyrosine, serine and threonine amino acids
there are receptor and non receptor protein kinases (majority non, cytosolic signalling proteins)
cytosolic protein kinases act as intermediaries once active they active other protein kinases, other signalling proteins or directly phosphorylate effector proteins like enzymes
phosphorylation of target proteins can either active or inactive them
some can enter nucleus but do not interact with DNA directly, can phosphorylate proteins that do
calcium binding proteins (signalling protein)
calcium kept at low intracellular concentration so when level increase due to signalling event, interact with certain proteins causing downstream effect
example
- CA2+ bind to calmodulin inducing conformational change that allows it to calmodulin to bind to target protein
adenylyl cyclase (signalling protein)
converts ATP into cyclic AMP (cAMP)
not linked to membrane receptors
binds to alpha subunit of heterotrimeric G proteins so designated as signalling protein instead of receptor type
subunits for adenylyl cyclase (signalling protein)
two types of heterotrimeric G protein alpha subunits
- as which stimulates adenylyl cyclase
- ai inhibits it
different forms of alpha subunit linked to different G protein coupled receptors
lipid kinases (signalling protein)
phosphorylate phospholipids in the cytoplasmic leaflet of membrnae
add phosphate to polar head group, results in conformational change in phospholipid allowing it to bind to target protein in membrane to pass signal
some phospholipids can be phosphorylated more than once to become an active signalling molecule
adaptor proteins (signalling proteins)
class of protein that is neither a receptor or enzyme
have different binding domains that recognize phosphorylated amino acids or other activated structures of signalling proteins
domains form the glue to hold elements of signalling networks together at right time and place in cell
important to allow cascade when and where needed
what are second messengers
they are non protein ions or molecules formed/release during signal transduction
relay signalling information from signalling proteins to other cellular targets
features of second messengers
small in size
rapidly diffuse in cytosol/membrane
amplify signals so the interaction of few ligands cause much larger response
do not live in the cytosol for long, degrade by specific enzymes (phosphodiesterase - cAMP/cGMP) or sequestered into cellular organelles (ionic messengers Ca2+)
heterotrimeric G protein signalling cascade
GPCRs (receptor)
- pathway start by binding of ligad on GPCR
- binding of receptor allows receptor protein to interact with heterotrimeric G protein
cAMP
- receptor stimulates replacement of GDP for GTP in alpha subunit
- heterotrimeric G protein dissociates from receptor leaving beta/gammer subunit and an activated alpha subunit
- alpha subunit finds and activates signalling protein adenylyl cyclase to convert ATP into cAMP (second messenger)
PKA
- cAMP binds to another protein kinase A (PKA)
- binding to regulatory subunits cases protein to dissociate and release the active catalytic subunit
- catalytic subunit phosphorylate number of cellular proteins
CREB
- active PKA catalytic domains can enter nucleus
- targets cyclic AMPA response elemement binding protein (CREB)
- PKA phosphorylate so CREB binds CBP (CREB binding protein) which interact with DNA to initiate transcription
phospholipid kinase signalling cascade
GPCR
- pathway start by binding of ligad on GPCR
- binding of receptor allows receptor protein to interact with heterotrimeric G protein
- receptor stimulates replacement of GDP for GTP in alpha subunit
- heterotrimeric G protein dissociates from receptor leaving beta/gammer subunit and an activated alpha subunit
PLC
- alpha subunits binds the phospholipid kinase signalling protein phospholipase C (PLC)
PIPI2/IP3
- activated PLC break down membrane phospholipid PIP2 to release two second messengers (disacyglycerol (DAG) and IP3)
Ca2+
- IP3 diffuses freely in cytosol to active ER receptors
- opens ligand gated calcium channel
- Ca2+ leaves ER acting as second messenger
- Ca2+ actives number of calcium binding proteins
PKC
- membrane bound DAG and Ca+ bind to protein kinase C (PKC)
- active PKC phosphorylate numerous cellular targets to modulate targets activity
protein kinase signalling cascade
FGFs
- fibroblast growth factors (FGFs) bind to FGF receptors
- FGFR is a homodimeric (two identical protein subunits)
- binding of FGF to FGFR cause subunits to dimerize (come together)
- FGFG undergoes tyrosine transautophosphorylation to form phosphotyrosines on cytoplasmic side
- phosphotyrosines can be bound by a multitude of proteins
Grb2
- adaptor protein Grb2 bind to phosphotyrosine causeing confromational change of Grb2 to bind Sos
- Sos bind to monomeric G protein Ras, replaces GDP with GTP
- Ras bind to serine/threonine kinase called Raf
- Raf can phosphorylate the protein kinase MEK
- MEK phosphorylate another serine/threonine kinase (Erk)
Erk
- Erk forms dimer and can phosphorylate signalling proteins in cytosol or nucleus
- can enter nucleus to active transcription factors
what are lysosomes
organelles that break down misfolded and damaged organelles, nucleic acids, lipids and more
what are proteasomes
protein complexes that specifically break down damaged and misfolded proteins in the nucleus/cytosol
digest both soluble proteins and membrane proteins in the lysosome
what are peroxisomes + function
small membrane enclosed organelle with enzymes
essential peroxisomes proteins called peroxins (synthesized in cytosol and targeted to peroxisomes by specific peroxisomal targeting signals (PTSs))
handle dangerous free radicals (reactive oxygen species) and important for decomposing some cargo (uric acid)
place to keep and use ROS safely
vesicles role in cargo delivery to the lysosome
engulfed proteins delivered by vesicles that empty their content by fusing with the lysosome and are digested by the proteases
protease delivered to the lysosome via vesicle
digestion in the lysosome
breakdown proteins not endogenous to the cell or from other cells
contain high concentration of proteases and enzymes that cleave and digest fats and sugars and can even engulf other organelles
one large molecules are broken down into basic parts, thy are transported to the cytosol for cell reuse
proteasome protein degradation
proteasome required process of ubiquitination (transcriptional modification of proteins)
misfolded/damaged cytosolic proteins tagged with polyubiquitin chain (required for protein to be targeted and recognized)
in nucleus unwanted nuclear proteins are polyuiquinated then degraded by nuclear proteasome
what is apoptosis
programmed cell death
energy consuming process that cleanly and carefully ends the life of a cell
protects the body from damaged cells
mechanisms of apoptosis
initiation
- initiated by two pathways (intrinsic, extrinsic)
membrane blebbing and enzyme activation
- cell shrinks and forms blebs (small protrusions from plasma membrane), first visible signal
- caspases enzymes activate
- initiator caspases cleave and activate executioner caspases
cell structure change
- executioner caspases activation causes cell structure change
- DNA is fragmented (often between histones)
- DNA repair stops
- nuclear membrane breaks down and the nucleus disappears
- cytoskeleton disassembled
- plasma membrane phospholipid content changed with scramblases (PS exposed on exoplasmic leaflet)
- organelles persist and are encloses in apoptotic bodies
phagocytes
- phagocytes endocytose the apoptotic bodies to dispose of them (safely digested by the lysosomes)
- minimal disturbance to cells and surrounding tissue
intrinsic pathway apoptosis
cell initiates it itself
pathway originates in outer membrane of mitochondria
intracellular signals (DNA damage, ROS toxins) turn on the pathway in the cell
extrinsic pathway apoptosis
external signals initiate apoptosis
pathway uses a plasma membrane receptor called death receptor
neighbouring cells release death ligand which bind to death receptor activating signals
what is necrosis
accidental cell death
result of severe cellular injury unable to be repaired
organelles cant function so it dies
injured cell response
attempt to repair
stressed cell show swelling in mitochondria and ER or some blebbing
if able to recover return to normal
causes on necrosis
- toxins
- extreme heat or radiation
- freezing
- ischemia
- pathogens
- mechanical trauma
mechanisms of necrosis
damage
- cell damaged beyond repair
swelling
- organelles lose structure and swell
- vacuoles or undefined bodies form in cell
- depending on damage DNA may degrade
destruction
- cell membrane and remaining organelles lose structural integrity
- cellular content spill, cause inflammatory signals
- mitochondria proteins released and lysosomal contents exposed
- cells nearby exposes and are damaged or apoptosis signalling is triggered
