Signal transduction Flashcards
Signal transduction
A way in which cells gain information about the environment
A way in which cells gain information about the environment
1. A ligand binds to a specific structural site (binding pocket) on the extracellular or membrane-spanning domains of the receptor.
2. Binding of a ligand to its receptor causes a conformational change of the receptor activating messengers
3. Ultimately induces specific cellular responses.
Why signal transduction relevant
Mediates direct cell-cell communication in adjacent cells.
Coordinates metabolic processes (plants & animals) within cells, the growth and differentiation of tissues, the synthesis and secretion of proteins.
Coordinates the aggregation of free-living cells for sexual mating or differentiation under certain environmental conditions in Eukaryotic microorganisms (e.g., yeast).
Signalling molecules and cell-surface receptors
Communication by extracellular signals usually involves the following steps:
Receptors activation occurs by:
1. binding of molecules (e.g., hormones, growth factors, neurotransmitters, pheromones),
2. changes in the concentration of a metabolite (e.g., oxygen, nutrients)
3. physical stimuli (e.g., light, touch, heat).
Generally, ligand binding to a receptor leads to activation of transcription factors in the cytosol, permitting them to translocate into the nucleus and stimulate (or occasionally repress) transcription of their target genes.
Signalling molecules functional range
In animals, signalling molecules can act over an array of distances. Signalling by soluble extracellular molecules can be classified into three types based on the distance over which the signal acts.
1. Endocrine
2. Paracrine
3. Autocrine
Endocrine signalling
The signalling molecules released by a cell affect target cells distant from the site of synthesis
Endocrine signalling example:
Hormones - in animals, endocrine hormones usually carried by the blood or by other extracellular fluids from its site of release to its target.
Paracrine signalling
The signalling molecules released by a cell affect target cells only in close proximity
Paracrine signalling examples:
Many growth factors regulating development in multicellular organisms act at short range.
Conduction by a neurotransmitter of a signal from one nerve cell to another or from a nerve cell to a muscle cell (inducing or inhibiting muscle contraction)
Some signalling molecules can act both short range and long range. Epinephrine, for example, functions as a neurotransmitter (paracrine signalling) and as a systemic hormone (endocrine signalling).
Autocrine signalling
Cells respond to substances that they themselves release.
Autocrine signalling examples:
Cultured cells often secrete growth factors that stimulate their own growth and proliferation.
Tumour cells overproduce and release growth factors that stimulate proliferation of themselves and adjacent nontumor cells - Leading to the formation of a tumour mass.
Intracellular signal transduction
Pathways inside the cell that transduce signals downstream from cell-surface activation
Binding of ligands (“first messengers”) to the cell surface receptors leads to a short-lived change in the concentration of low-molecular-weight intracellular signalling molecules (”second messengers”)
The altered intracellular concentration of one or more second messengers leads to the activation of an intracellular protein within the signal transduction pathway.
- Secondary messengers = cyclic nucleotides, such as cAMP, cGMP, lipid messengerssuch as DAG, IP3, ions such as Ca2+
Adenyl cyclase pathway
- External signal (epinephrine = adrenaline) binds to the G protein-coupled receptor.
- G protein activates adenyl cyclase (enzyme that synthesizes cyclic adenosine monophosphate (cAMP) from adenosine triphosphate (ATP).
- Adenyl cyclase releases cAMP (functions as a second messenger to activate intracellular effectors, particularly protein kinases)
4 Released cAMP activates protein kinase A - Protein kinase A activates enzyme within the pathway
- Enzyme produces the desired product.
Proteins that help transduce signals downstream from activated cell surface
G proteins - guanine nucleotide-binding proteins also known as molecular switches, belong to the larger group of enzymes calledGTPases
Protein kinases - enzymes that catalyse the addition of phosphates to a substrate protein
Phosphatases - enzymes that catalyse the removal of a phosphate from a substrate protein
G protein
G Proteins interact with other proteins downstream of the signal transduction pathways to change and perpetuate the signal (transduce).
the G protein has to switch between an “on” or “off” state
GTP-bound “on” state or GDP-bound “off” state.
In the active “on” state, two protein domains, are bound to the terminal phosphate of GTP allowing the protein to bind to and activate other downstream signalling proteins (3 phosphates - guanosine triphosphate)
Release of the phosphate by GTPase-catalysed hydrolysis causes domain I and II to relax into the GDP or inactive “off” state. (2 phosphates - guanosine diphosphate)
Protein kinases and phosphatases
Activation of all cell- surface receptors leads directly or indirectly to changes in protein phosphorylation through the activation of protein kinases or protein phosphatases.
Protein Kinases
- Two types in animal cells
- Add phosphate group (phosphorylate) to the hydroxyl group on tyrosine residues (on state)
- Add phosphate group (phosphorylate) to the hydroxyl group of serine and threonine residues (on state))
Protein Phosphatases
- Remove phosphate groups (dephosphorylate) (off state).
G protein-coupled receptors
All G protein–coupled receptors (GPCRs) contain seven membrane-spanning regions, N-terminal segment on the exoplasmic face (outside the cell), C-terminal segment on the cytosolic face (inside the cell) of the plasma membrane
GPCR family includes:
receptors for numerous hormones and neurotransmitters,
light-activated receptors (rhodopsins) in the eye,
literally thousands of odorant receptors in the mammalian nose.
The rhodopsin-mediated signal transduction cascade in rods and rod bipolar cells (adapted from Pahlberg and Sampath, 2011). As light is absorbed by rhodopsin, a G-protein-coupled receptor (GPCR), the activation initiates an exchange of GTP and GDP.
The cGMP is hydrolyzed by a cGMP phosphodiesterase complex (PDE complex).
This reduction in the concentration of cGMP will close the cGMP-gated channels, which function to depolarize the membrane potential of rod bipolar cells via influx of Na + and Ca 2+
Ligand induced activation of effector proteins associated w G protein coupled receptors
The trimeric G proteins are tethered to the membrane by covalently attached lipid molecules (wiggly black lines).
1. Ligand binds receptor
2. Receptor binds G protein
3. Exchange of GDP with GTP (G protein is activated)
4. Alpha part of the G protein binds to and activates an effector protein.
5. Hydrolysis of GTP terminates signalling leading to reassembly of the trimeric form, returning the resting state.
Effectors can be both activated or inhibited by G protein coupled receptors
G proteins can activate ion channels
Binding of acetylcholine triggers activation of the G protein.
The released G-beta subunit (rather than G-alpha) binds to and opens the associated effector, a K+ channel.
e.g light activated G protein coupled receptors:
- The human retina contains two types of photoreceptors, rods and cones, that are the primary recipients of visual stimulation.
- Cones are involved in colour vision (GPCR = iodopsin).
- Rods are stimulated by weak light (GPCR = rhodopsin).
- Rhodopsin, a G protein–coupled receptor that is activated by light, is localised to the membrane disks of rod cells.
- The trimeric G protein coupled to rhodopsin, often called transducin (Gt), is found only in rod cells
In dark-adapted vision high levels of cGMP keep the nucleotide-gated non-selective cation channels open
1. Retinal molecule inside an opsin proteinabsorbs light activating it
2. Activated opsin binds the G protein mediating GDP to GTP replacement
3. The free alpha subunit of the G protein activates cGMP phosphodiesterase (PDE) by binding its inhibitory gamma subunit
4. The PDE inhibitory gamma subunits dissociate from the catalytic alpha and beta
5. No longer inhibited, the alpha and beta subunits convert cGMP to GMP
6. Decrease in cGMP in the cytosol leads to dissociation of cGMP from the nucleotide-gated ion channel closing the channel, hyperpolarising the membrane
