Signal transduction & biochemical defence Flashcards
(41 cards)
Give three examples of stimuli that would trigger a response.
- Light
- mechanical touch
- pathogens
- Tastants
- Neurotransmitters
- Nutrients
- Odorants
What are the eight concepts/features of signal transducing systems? Explain them in short.
a) Specificity: That the receptor and signaling molecule fits well together (many small non-covalent interactions) while other signaling molecules don’t.
b) Sensitivity: That the signaling molecule have a high affinity to the receptor, favoring binding.
c) Amplification: That the activation of one enzyme can activate more to make the response bigger, fast, in an enzymatic cascade.
d) Modularity: That the receptors can be assembled differently to convey different signals/responses. Modifications like phosphorylation provides reversibility of assembly.
e) Desensitization/adaptation: Receptor activation triggers feedback inhibition that turns off the receptor activity or removes it, to limit response and make the cell sensitive to size of stimuli.
f) Integration: Multiple signals are summed so that the resulting response comes from the integrated input from both signals.
g) Divergence: One signal can convey more than one response, eg to activate one process and inhibit another.
h) Localized response: When the receptor is clustered with the enzyme that shuts of the signal, the signal is confined locally and doesn’t spread.
Name the four receptor types present in multicellular organisms.
- Gated Ion channels: Opens or closes in response to concentration of small ligand or membrane potential change.
- GPCRs (G-protein coupled receptors): External ligand binding activates an internal G-protein that in turn activates an enzyme generates a second messenger which conveys signal.
- Receptor tyrosine kinases: external ligand binding activates internal tyrosine kinase activity by autophosphorylation.
- Nuclear receptors. Intracellular receptor that act in the nucleus as transcription factors to regulate gene expression upon binding of hormones.
How does gated ion channels work in short?
- Gated ion channels are found in excitable cells, like nerve cells, muscle cells and hormone releasing cells.
- They provide a regulated flow path for ions in response to stimuli, most common; Na+, K+, Ca2+ and Cl-.
- Those regulated by changed membrane potential are maintained by pumps that keep the membrane potential up, so that a signal can be relayed.
Explain how gated ion channels work with a real life example.
A good example of gated ion channels are those in nerve cells, both in axon and synaps.
The action potential needed to relay the signal to the next neuron is dependent on voltage gated Na+ channels. They are closed when membrane potential is at resting potential (maintained by ion pumps) and opened when the membrane is depolarized. With the opening of a Na+ channel, the membrane in it’s close vicinity is opened, and the next is open, this moves the action potential through the axon to the synapse.
- In the synapse, there are voltage gated Ca2+ channels, and when the membrane is depolarized at the synapse, these open and results in a big influx of Ca2+.
- The high concentrations of Ca2+ triggers the fusing of NT filled vesicles to the synaptic membrane, releasing the NTs (ACh in this example) in the synaptic cleft. There, the ACh bind to ligand gated Na+ channels which open and an influx of Na+ cause a new action potential in the next neuron and signal is relayed.
Ca2+ usually have this role in other vesicle systems too!
How does the binding of ACh affect the ligand gated ion channel?
When Ach binds, the alpha helices that form the channel change conformation, so that other residues (hydrophilic) are pointed inwards, which can let through specific ions.
Explain how GPCRs work with a real life example.
A classic example of a GPCR signal relay system is beta-adrenergic receptors (epinephrine binding). Epinephrine (adrenaline) binds to the GCPR, and the binding causes a conformational change in the ligand binding part causes a change in the G-protein, that lowers its affinity to GDP and increases its affinity to GTP. When GTP binds, the alpha subunit of the G-protein disassociates and activates adenylyl cyclase, which in turn catalyzes the formation of cAMP (2nd messenger) that activates PKA that phosphorylates enzymes (amplification) that for example mobilize energy metabolism (FA synthesis and glycolysis for example) and shuts down energy requiring processes, basically causes the whole response to adrenaline.
How is the activated G-protein inactivated?
The activated G-protein is inactivated by intrinsic GTPase activity, which reforms GDP and cause it to reassociate with the GPCR.
Explain how receptor tyrosine kinases work with a real life example.
An example of receptor tyrosine kinases is the insulin receptor. When insulin binds to the external portion, the internal part of the receptor dimerizes and undergo autophosphorylation on its c-terminal tyr residues, forming a complex with kinase activity. The kinase phosphorylates IRS-1 (intracellular protein) which forms a complex that move on to bind to Ras. The binding to Ras causes a conformational change so that it has higher affinity to GTP than GDP, and is activated. Activated Ras binds and activated Raf-1, which phosphorylated MAK, which in turn phosphorylates ERK that moves into the nucleus and phosphorylates TFs that stimulate transcription of cell division genes.
How exactly does the autophosphorylation of the tyr residues on the receptor tyrosine kinase activate it?
The conformational changes brought on by the phosphorylation of the three tyrosine’s in each part moves an Asp that blocks the active site away, unblocking it so the the target substrate can bind.
Explain how nuclear receptors work in detail.
- A hormone bound to a serum binding protein is released in the target tissue, and the small and non-polar hormone diffuses through the outer membrane into the nucleus.
- In the nucleus, it binds to a nuclear receptor, which changes the conformation of the receptor so that it forms dimers with other hormone-receptor complexes which binds to HREs (Hormone responsive elements) in the DNA adjacent to specific genes.
- The receptor-hormone complexes attracts coactivator/corepressor proteins and with them, regulates transcription of the adjacent gene(s), increasing or decreasing the rate of mRNA formation.
- The altered levels of the gene produce a cellular response to the hormone. (a lot slower process than the membrane bound receptors).
Recognition – vs binding affinity. Are they related, interdependent? What happens if signals…
- …are interpreted wrongly?
- …trigger unjustified response?
It is important for receptors to have high specificity, but if the binding affinity is too high, that would lead to the triggering of bigger responses than needed. So a balance is needed!
What are hormones?
Hormones are chemical messengers that activate cellular responses in other tissues than where they’re synthesized. They are a diverse group of molecules including peptides, amines, eicosanoids etc. Signaling can be either via nuclear receptors (small non polar hormones) or membrane bound receptors + 2nd messenger.
Give one example of a steroid hormone and one peptide hormone.
Sterioid: Estradiol, testosterone
Peptide: insulin, glukagon, some NTs.
Peptide hormones often go through post-translational modifications to get to their active form. Name and explain the process of one.
Insulin is modified post translationally. It is translated as preproinsulin, a signal sequence is cleaved away to form proinsulin and then the C-peptide is removed to form the tertiary structure of insulin.
Hormones are excreted from endocrine organs, name three and what hormone they excrete.
- The pancreas release glucagon and insulin.
- the testis and ovaries release testosterone and estrogen.
- The adrenal glands release epinephrine.
Hormones have a hierarchy, what does this mean?
Hormonal signaling is dependent and regulated by other hormonal signaling. So the stimuli that the hormonal signaling is the response to comes into the central nervous system, which in turn triggers the release of hormones from the hypothalamus –> pituitary and from there the hormones stimulates a range of hormones depending on the stimuli.
Some metabolism is tissue specific, name three tissues that are central in metabolism of proteins, lipids and carbohydrates.
- The liver is the most important metabolically active tissue. The portal vein is a direct route from the digestive organs to the liver, and the liver therefore has first access to ingested nutrients. The liver is responsible for urea excretion and recycling of amino acids AND glucose and lipid synthesis. All these processes produce base materials for synthesis of nucleotides and other important compounds too. The liver has amazing metabolic plasticity, with an enzyme turnover rate 5-10 times faster than other tissues.
- Adipose tissue stores, mobilizes and synthesizes lipids.
- The pancreas release glucagon and insulin which is central in glucose homeostasis.
Explain the Cori cycle in short.
The Cori cycle is the pathway for extra energy supply in muscle. At rapid contractions in muscle, the muscle start to break down glycogen to produce ATP anaerobically, forming lactate in the process. The lactate is then transported via the blood as blood lactate to the liver, where the lactate is converted to glucose via gluconeogenesis. The glucose is then transported to the muscles again to reform the glycogen used up for rapid contractions.
Explain the metabolic pathway for glucose from ingestion, through liver out in the body.
When carbohydrates are broken down in the GI system, the monosaccharides are taken up in the epithelial cells of the intestine and transported via the portal vein to the liver. In the liver, the glucose is quickly phosphorylated by hexokinase IV into Glucose-6-phosphate. From there, depending on the energy state:
1. If glucose is scarce, dephosphorylation happens to yield free glucose that can diffuse out into the blood.
2. Glucose 6-phosphate not immediately needed to form blood glucose is converted to liver glycogen, or has one of several
other fates:
3. Go through glycolysis and PDHc to form Acetyl-CoA that go into the CA cycle + ETC to provide energy to the hepatocytes. (Normally, however, fatty acids are the preferred fuel for ATP production in hepatocytes, as other tissues have high glucose needs)
4. Acetyl-CoA can also serve as the precursor of fatty acids, which are incorporated into TAGs and phospholipids, and of cholesterol. Much of the lipid synthesized in the liver is
transported to other tissues by blood lipoproteins.
5. Go through the PPP (pentose-phosphate pathway) and form Ribose-5-phosphate used in nucleotide synthesis.
What is the normal range of blood glucose concentration (in mg/100mL)?
90-60 mg/mL is considered normal, below that we get subtle neurological signs of energy depletion like hunger, trembling, sweating and this is where glucagon, epinephrine and cortisol are released. Below 40 is critical, and lead to lethargy/coma and prolonged time below can lead to brain damage or death.
The rather small differences between these states is the reason for very tight regulation to maintain glucose homeostasis, mainly by the hormones insulin and glucagon.
In what organ and what cells is glucagon and insulin synthesized?
Both insulin and glucagon are produced in the pancreas:
- β cells produce insulin
- α cells produce glucagon
Both of these cell types exits as islets - small “colonies” of the same cell type in a cluster.
How is insulin secreted?
When the blood glucose levels are high, a lot of glucose is taken up by the pancreatic β cells, in there, its phosphorylated to glucose-6-phosphate which goes through glycolysis + Ca + oxidative phosphorylation which higher the ATP levels in the cell. The high levels of ATP inhibits ATP gated K+ channels in the outer membrane, which causes depolarization of the membrane. The depolarization causes voltage gated Ca2+ channels to open and the influx triggers fusion of ER vesicles filled with insulin to fuse with the outer membrane and release the insulin out in the blood to different targets, promoting synthesis and storage of energy rich molecules and downregulation of their breakdown.
Glucagon basically have the reverse effect.
What happens in the liver at a well fed state?
During a well fed state, the metabolism is focused on energy storage. Insulin release stimulates several metabolic processes in the liver:
- Glucose uptake
- Glycogen synthesis
- Glycolysis -> Acetyl-CoA -> Fatty acid synthesis (a little for fuel)
- TAG (triacylglycerol) synthesis and storage in adipose tissue.
All of this contributes to lowering the blood glucose levels which eventually stops insulin release (so kind of feedback regulation)
