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Cell signalling - Coggle Diagram

- - - - temperature, light, pH, salinity, hydration
      - environment is ever changing and to detect and respond to this is crucial for survival
    - - hormones, growth factors and neurotransmitters
      - position and function in the organism is achieved by "social control" where cells signal their status to other cells
  - - - coordinates cell behaviour over long distances, the signalling molecules are synthesied and secreted by signalling cell nad transport through circulatory cells
      - slow signalling and dilute at receptor
      - insulin secreted by pancreas and epinephrine secreted by adrenal glands are signals that travel through the blood
      - defects in endocrine signalling can lead to diabetes
    - - acts over small distances from the cell released from
      - neuron releasing a neurotransmitter that acts on adjacent neuron; many protein growth factors regulate development also have short range
      - some developmental signalling proteins form concentration gradients that induce different responses depending on local concentration and so distance
      - TGF-Beta are secreted by a cell and then are trapped in extracellular matrix until freed to bind to surface receptors
    - - these cells respond to substances that they release themselves
      - this is most common in groups of cells that enable that group to enter a specific development pathway like insulin growth factos in muscle development
      - many tumour cells release growth factors that stimulate unregulated self-proliferation
      - Eicosenoids are fatty acid derivatives made by all mammalian tissue cell which increase in production in autocrine fashion to mediate pain, fever, and inflammation
      - sometimes there can be proteolytic cleavage of a membrane-bound signalling protein which releases teh extracellular domain which then functions as a soluble signalling molecule that can act locally or at distance
  - - - poorly understood range and type of biomolecules used to communicate in active microbial communities
      - example-quorum sensing in pseudomonas aeruginosa and communicate with one another, that allows a coordinated virulence response
    - - well studied role of mating factors in Saccharomyces cerevisae that signal cells of opposite mating type to stop proliferating in preparation for sexual mating
      - well studied role of cAMP in starvation response of dictyostelium discoideum which leads to aggregation forming a stalk and fruiting bodies which are resistant
    - - very well studied because of clinical role but knowledge far from complete
      - knowledge improved because the receptor and pathways are highly conserved and function in similar way for lots of organisms
  - - - Diffusion of hydrophobic signal (steroids, retinoids, vitamin D, thryoxine) through plasma membrane
      - binds to cytosolic receptor
      - receptor-signal complex movers into nucleus and binds to transcription-control regions in DNA to change expression by changing conformation allowing co-activators to bind and induce transcription
    - - signal binds to specific cell-surface receptor proteins and triggers receptor conformational change that activates receptor
      - activated receptor activates one or more downstream signal transduction proteins or small second messengers
      - signal transduction proteins or second messengers activate one or more effector proteins
      - effector
        
        can stimulate modification of cytosolic proteins to produce short-term changes in cellualr function
        
        or can move into nucleus and trigger long term changes in gene expression by activation/repression of transcriptional factors
        
        changes to proteins are initiated by covalent modifications like phosphorylation or ubiquitinoylation or ion binding
      - negative feedback mechanisms and eventual destruction of extracellular signals
  - - - generally consist of three discrete topological domanis
      - extracellular domain, plasma-membrane spanning domain, intracellular domain
      - binding site may be in extracellular or membrane-spanning domain
      - binding of ligand causes conformational change transmitted to cytosolic domain which either activates or inhibits other proteins (usually through protein phosphorylation)
      - the site that interacts with next molecule is not site where ligand binds so receptors are allosteric
    - - Ach
        
        skeletal muscle- release of Ach from motor neuron (paracrine signalling) triggers muscle contraction by activating an ion channel
        
        heart muscle- release Ach by certain neurons activates a G protein-coupled receptor that opens K+ channel, reducing rate of contraction
        
        pancreatic acinar- Ach binding induces rise in Ca2+ concentration in cytosol that triggers secretion of digestive enzymes to facilitate digestion
      - epinephrine
        
        Liver and muscle- stimulates depolymerisation of glycogen to glucose
        
        adipose cells- secretion of stored fat
      - identical receptor on different cells but same internal signalling machinery gives distinct response, this is effector specificity
      - the response of a cell is a combination of signalling molecules is the subset of receptors that the cell possesses to detect the signals and nature of intracellular machinery
    - - it is qquantified by the dissociation constant (Kd)
      - Kd= [R][L]/[active R-L complex]
      - lower Kd value the tighter the binding and more stable the complex
  - - - transfers phosphate from ATP (form ADP) to specific Ser/Thr or Thr-OH
      - phosphorylated residue is part of specific kinase target motif
      - this activates the protein
      - they all have a nucleotide-binding pocket that binds ATP to position gamma phosphate to be transferred to OH moiety of substrate
      - Protein Kinase A
        
        it is a kinase that phosphorylates proteins that regulates metabolism
        
        when inactive critical residues in activation loop or in wrong position to bind to ATP and protein substrate
        
        when a critical threonine residue in activation loop is phosphorylated by PKA, the loop conformation changes creating binding site for ATP and substrates
      - glycogen phosphorylases kinase
        
        activated by signal transduction pathway it phosphorylates adn activates the enzyme to break down glycogen
        
        the addition of phosphate group to an amino acid creates a binding surface to allow second protein to bind
    - - hydrolyses P off Ser/Thr or Thr-OH
      - this inactivates the target protein
  - - - turning on
        
        GTP is bound
        
        turning on is promoted by GEFs which catalyses dissociation of bound GDP and replacement by GTP (not phosphorylation of GDP)
      - turning off
        
        GDP is bound
        
        turning off is controlled by GTPase activity which is accelerated by GAPs and RBSs
      - they are G proteins
        
        Heterotrimeric G proteins are activated by direct interaction with surface receptors. GEFs activate the heterotrimeric G protein to which they are coupled by triggering its release of GDP and binding of GTP induces conformational change
        
        Monomeric G proteins are activated by GEFs that are activated by surface receptors or other proteins. They do not directly bind to receptors but act as intermediate proteins in signal transduction pathways
  - - - sympathetic stimulation leads to relaxation becuse of rapid turnover rates of NO and cGMP
      - mediated by nitrate/nitrite conversion and cGMP phosphodiesterase
      - Viagra is an inhibitor of cGMP phosphodiesterase, so half life for cGMP rises and it persists in cell keeping blood vessels relaxes and increasing blood flow to the penis
- - - - SERCA actively transports Ca2+
      - Calreticulin is a chaperon protein so Ca2+ is not left as a free ion
  - - - Neural involves Ca2+
      - Hormonal involves stimulation of beta-adrenergic receptora to produce cAMP
  - - - it has 4 EF hand-helix domains
      - it can bind Ca2+ which induces a conformational change which leads to ability to bind helices from specific proteins
      - bidning of 4 ions changes the shape so that it forms a ring like structure which allows it to recognise certain protein regions and peptides in the cell context
    - - Structure
        
        6 identical subunits
        
        it is inactive when there is no calmodulin, change in shape allows binding
      - Calmodulin binding
        
        first binds to 4 calmodulin which activates it and autophosphorylates (at tyrosine 286)
        
        this changes conformation so 6 calmodulin bind, but then they disassociated to give a singly phosphorylated complex
        
        it then further autophosphorylates at tyrosine 306 and 307, the complex is now active and calmodulin can no longer attach
        
        phosphatases removes phosphates and inactivates it
      - Neurotransmission
        
        when CaMKII moves into spine head of neurone it becomes activated
        
        Activity
        
        interfere and modulate RAS-ERK signalling
        
        NMDA receptor interacts with CaMKII at synapse and opens calium channel cauing influx (this is under positive feedback since more Ca, means more CaM, and CaMKII)
        
        AMPA receptor cofactor Stargazin is phosphorylated which allows it to bind to PSD85 which moves the AMPA receptor to the synapse. Phosphorylation of GluR1 S831 increases averase single channel conducatance of AMPARs which causse Ca influx by changing electrical polarity which underwrites neural activity
    - - legumes: central to synbiotic relationships between legumes and bacterial and arbuscualr mycorrhizae
      - CaMK activated calmodulin phosphorylates the transcriptional factor CYCLOPS to activate notive inception NIN or educed arbuscular mycorrhiza RAM1 gene
- - - - consists of 2 R subunits and 2 C subunits
      - each R has 2 cAMP binding domains (CNB-A and CNB-B) and a linker domain
      - at C terminus there is dimerization domain that binds an AKAP protein
      - segment of CNB-A domain is a pseudosubstrate (sequence that binds to active site but is not phosphorylated) and in absence of cAMP it binds to catalytic site and inhibits its activity
    - - it is turned on by elevations in cAMP levels, binding of cAMP to CNB-A causes conformational change so it no longer inhibits catalytic site
      - this releases the C subunit which activates kinase activity
      - cAMP binds to R subunit so that binding of first cAMP to CNB-B lowers Kd so stimulates binding of second and release of R subunit from kinase
      - small changes in cytosolic cAMP cause relatively large changes in kinase activity
    - - anchoring proteins confine some PKA to specific locations in cell since response may only be required in one area
      - they are anchoring proteins with 2 domain structure
      - can also anchor cAMP phosphodiesterase which hydrolyses cAMP to AMP so confines PKA activity to short bursts
- - - - Family A
        
        side chains of 15 amino acids on helices and loops bind to ligand
        
        2 hydroxyl groups on epinephrine binds to 2 Ser residues and 1 Asp
        
        B-adrenergic receptors binds epinephrine and norepinephrine
      - Family B
        
        glucagon receptor binds to glucagon (a 29 amino acid hormone)
        
        it also has 7 transmembrane a-helices but also has large exoplasmic domain that is connected to first a-helices which binds to C-terminus of glucagon to position N-termiuns to bind to pocket
      - Family C
        
        glutamate receptor is excitatory neurotransmitter receptor
        
        teh long extracellular segment forms a clamp that binds to glutamine
  - - - conatin 3 subunits a, B, y
      - a subunit binds to either GDP or GTP
      - B and y subunits have covalently attached fatty acids that insert inot the inner leaflet
      - humans have 21 a, subunits encoded by 16 genes (gene splicing)
    - - GDP is bound to a subunit
      - it has no complementary to the G protein and cannot to bind to it
    - - binding of ligand to GCPR alters conformation of transmembrane helices
      - this enables the receptor to bind to the a subunit of heterotrimeric G protein containing GDP
      - binding of GCPR to a subunit changes conformation allowing a lobe of the protein to move and release GDP
      - the high GTP concentration means it binds to the empty G site in a subunit
      - GTP binding to a subunit causes conformational change so it dissociates from By subunit, the freed activated GCPR can activate another heterotrimeric G protein