Lecture 14 Flashcards
cell signalling
a signal transduction pathway is a series of steps by which a signal on a cells surface is converted into a specific cellular response
Stages of cell signalling
reception
transduction
response
discovery of the three stages of cell signalling
in 1971 an American biochemist won the Nobel prize for his discovery of how the hormone epinephrine acts on cells
Sutherland suggested that cells receiving signals went through the three processes
Stage 1- reception
reception is the target cells detection of a signal molecule coming from outside the cell
the signal is detected when it binds to the membrane protein
Reception process
a signal molecule binds to a receptor protein causing it to change shape
the binding between a single molecule (ligand) and receptor is highly specific
a shape change in a receptor is often the initial transduction of the signal
most signal receptor are plasma membrane protein
Three main types of membrane proteins
G protein-coupled receptors
receptor tyrosine kinases
ion channel receptors
G-coupled receptor
a plasma membrane receptor that works with the help of a G protein
the G protein acts as an on/off switch: if GDP is bound to the G protein, the G protein is inactive
G-coupled receptor steps
- when GDP is bound to the G protein its inactive
- when the signalling molecule binds to the receptor it activates it and causes it to change shape. this change causes GDP to be released from the G protein and GTP to bind instead- activating the G protein
- the activated G protein dissociated from the receptor, and binds to another enzyme causing a shape change and activation in that enzyme- this triggers a signal cascade
- eventually the GTP is released from the G protein, GDP binds instead and the G protein returns to its inactive state
Retinal and Rhodopsin
-11-cis and all trans retinal and the crystal structure of bovine rhodopsin
light causes the conversion 11-cis retinal to all trans retinal
this in turn causes a conformational change in rhodopsin
this leads to activation of its G protein on the intracellular side- as in all GPCRs
G-protein linked receptors
contain 7 alpha helices spanning the membrane
coupled to a G-protein (acts as a switch)
Receptor tyrosine kinases
can trigger more than one signal transduction pathway one amplifying signal
the receptor itself has enzymatic activity
intracellular part catalyses transfer of phosphates to tyrosine residues
Ligand-gated channels
ligands acts as a gate to allow passage of ions through channels
Receptor tyrosine kinases (RTKs) steps
- during inactivity, the receptors exist as single units called monomers
- when the signalling molecule binds to the extracellular part of the receptor it triggers dimerisation of the RTK
- this causes activation of the intracellular part- the tyrosine kinase region- by adding phosphate groups to itself (activating it)
- the activated regions the trigger activation of subsequent downstream enzymes, setting off a phosphorylation cascade and transduction of a signal cascade
Ligand gated ions steps
- in the absence of the ligand the gate is closed to the ions
- when the ligand binds it causes shape change that opens up the gate to allow the ions through, the ions effect a cellular response
- when the liand is released (or cleaved) from the receptor, it closes the gat so the ions can no longer pass through
Protein phosphorylation and dephosphorylation
in many pathways, the signal is transmitted by a cascade of protein phosphorylation events
protein kinases add phosphates to a protein, this activates the protein
protein phosphatases remove phosphates from proteins, this deactivates the protein
this phosphorylation and dephosphorylation system acts as a molecular on/off switch
A phosphorylation cascade
- a series of different molecules in a pathway are phosphorylated inn turn, each molecule adding a phosphate group to the next one in line
- active forms of each molecule have phosphates attached and are of a slightly different shape
- the activation cascade continues until the signal reaches the nucleus (or another target) and causes the change in cellular activity
Intracellular receptors
found in the cytoplasm or nucleus of target cells
small or hydrophobic chemical messengers can readily cross the membrane and active receptors
an activated hormone-receptor complex can act as a transcription factor, turning on or off specific genes
Tranduction
the binding of the signalling molecule changes the receptor protein in some way, intimating the process of transaction
the transduction stage converts the signal to a form that can bring about a cellular response
Multiple step signal transduction
the molecules involved are mostly proteins
multistep pathways can amplify a signal: a few molecules can produce a large cellular response
at each step the signals is transducer into a different form, usually a shape change in a protein
multistep pathways provide more opportunities for coordination and regulation the cellular response
–> not just relay but amplification of the signal and modulation of the response
Response
the transducer signal brings about a cellular response: a change in cellular activity change in cytoskeleton or activation of genes in the nucleus
Cell signalling and regulation of transcription or cytoplasmic activities
the cells response to an extracellular signal is sometimes called the output response
ultimately, a signal transaction pathway leads to regulation one or more cellular activities
the response may occur in the cytoplasm or may involve action in the nucleus
many signalling pathways regulate the synthesis of enzymes or other proteins usually by turning genes on or off in the nucleus
the final activated molecule in the cascade may function as a transcription factor
Typical signalling pathway that leads to the regulation of gene activity in nucleus
- the initial signalling molecules, the growth factor, triggers a phosphorylation cascade
- once phosphorylated the last kinase in the sequence enters the nucleus and activated a transcription factor
- this activated transcription factor molecule then stimulated transcription of a specific gene or genes
- resulting in mRNA, then synthesis of a protein
Two important benefits of multistep pathways
amplification of the signal
- at each step the number of activated products is much greater than in the preceding step
- because the active form of the protein is present long enough to activate more than one molecule at the next stage of the pathway, before they become inactive again
contribution the specificity of the response
- different kinds of cells have different collections of relay proteins
-these different proteins allow cells to detect and respond to different signals
- event the same signalling molecule can have different effects in cells with different proteins and pathways
-pathway branching and ‘cross-talk’ further helps the cell coordinate incoming signals
Specificity of signalling
the particular type of proteins a cell possesses can determined what signalling molecule it responds to and the nature of the response
these 4 cells are all responding to the same signal molecule but in different ways
this is because the cells all contain different signalling proteins
some can inhibit other proteins and some can work together with other proteins to give a different response
Second messengers
many signalling pathways involve 2nd messengers
these are small, non protein, water-soluble molecules or ions that spread throughout a cell by diffusion
2nd messengers participate in pathways initiated by GPCRs and RTKs
Cyclic AMP and calcium ions are common second messengers
Cyclic AMP
cAMP is one of the most widely used 2nd messengers
adenylyl cyclase, an enzyme in the plasma membrane converts ATP to cAMP in response to an extracellular signal
Calcium ions
are used widely as 2nd messengers
ca2+ can function as second messengers because its concentration in the cytosol is normally much lower than the concentration outside the cell
a small change in the number of calcium ions thus represents a relatively large change in calcium concentration
Reversible cell damage
biochemical themes of reversible cell injury:
-ATP depletion
-Cellular swelling caused by changes in ion concentration
- changes in membrane permeability
Necrosis and apoptosis
differ in their morphology, mechanism and roles in disease and physiology
Apoptosis
programmed or controlled cell death
a cell is chopped and packaged into vesicles that are digested by scavenger cells
prevents enzymes from leaking out of a dying cell and damaging neighbouring cells
Caspases
the main proteases that carry out apoptosis
