Key Area 4
(c) Hydrophilic signals and transduction
Scotland plays a key role in vital research into cell signalling from understanding fundamental cell processes to treating and curing complex diseases. Institutes across our country are world-leading and this article showcases the leaps made in diabetes management through research into insulin signalling pathways.
Hydrophilic signalling molecules
Hydrophilic extracellular signalling molecules bind to transmembrane receptors and do not enter the cytosol. This is because their chemical nature means they cannot cross the phospholipid bilayer or be in contact with the intracellular milieu.
As a consequence, such signalling molecules must engage with surface receptors and transduce their effects by alternative process - this is known as signal transduction.
These signal transduction pathways can be incredibly complex, as illustrated in the diagram of insulin signalling, shown opposite.
Peptide hormones and neurotransmitters are examples of hydrophilic extracellular signalling molecules.
Hydrophobic signalling pathway
As discussed previously, a hydrophobic signalling molecule crosses the membrane, engaged with an intracellular receptor to form a complex that then binds to HREs on DNA to alter transcription.
Hydrophilic signalling pathway
Transmembrane receptors change conformation when the ligand (signal molecule) binds to the extracellular face. Transmembrane receptors act as signal transducers by converting the extracellular ligand-binding event into the intracellular signals, which alters the behaviour of the cell.
These activated intracellular signalling proteins might be G-proteins or cascades of kinase enzymes that catalyse phosphorylation.
Task 61
"Miss, do you remember when you used to put these things on bits of paper and we got to move them around and sort them into columns on the table? That was good effort from you", Big Davie said as he looked at the latest task. "Aye, I think you should do that again for us. We'd appreciate that".
"Would you really Big Davie? Printing out, laminating, cutting, putting into wee bags? I'll do it next time", replied Dr McRobbie. "But, for now, just because you're so lovely, could you please arrange the following statements under the headings "Hydrophobic signalling molecule" or "hydrophilic signalling molecule".
"Aye, alright Miss, but just because you're one of the good guys".
Here are the statements below. Now try and sort these into the column like Big Davie.
Cross the cell membrane
Do not cross the cell membrane
Intracellular receptors
Form receptor/signal molecule complexes and bind to HREs on DNA
Can activate G-protein cascade
Can activate phosphorylation cascades
Can directly affect gene expression
Examples include steroid hormones, e.g. testosterone
Examples include peptide hormones, e.g. insulin
Answers are available here.
G Proteins
G-proteins relay signals from activated receptors (receptors that have bound to a signalling molecule) to target proteins such as enzymes and ion channels.
In the image shown, a signalling molecule binds to the receptor protein. The protein will change conformation and GTP will bind to the G protein (displacing GDP). When this happens, the alpha subunit of the G protein binds to an effector protein that becomes activated. In this particular example, this activated "effector protein" then activates an ion channel, that enables the influx of ions into the cell.
Task 62
Watch the following video and write a step-by-step guide to summarise the role of G proteins in transducing extracellular hydrophilic signalling molecules into intracellular responses.
Suggested answers are here.
Phosphorylation cascades
Phosphorylation cascades allow more than one intracellular signalling pathway to be activated.
Phosphorylation cascades involve a series of events with one kinase activating the next in the sequence and so on.
Phosphorylation cascades can result in the phosphorylation of many proteins as a result of the original signalling event.
The image opposite exemplifies this. A hydrophilic signal molecule, growth factor, binds to its membrane receptor. The membrane receptor changes conformation and activates a phosphorylation cascade. This results in the phosphorlyation and activation of two proteins:
MNK1 - this increases translation of proteins on cytosolic ribosomes involved in cell growth and division
c-Myc - this increases transcription of genes involved in cell growth and division.
Task 63
"Oh aye Miss, check out this Big Davie, wit you daeing to me here. I'm no happy about another Big Davie in the room".
Dr McRobbie smiled, unsurprised. "Big Davie, meet Professor Dave - take a few minutes out to listen to his summary of signalling proteins. Add any notes that help you understand this topic better. Another very useful and insightful Dave from whom we always can learn something!"
Make your own notes for this part.
Case Study - Let's focus on Insulin
Insulin is a peptide hormone and is an example of a hydrophilic signalling molecule. It is one of the hormones involved in the homeostatic control of blood glucose concentration. Insulin is produced by pancreatic cells and released into the bloodstream under conditions elevated blood glucose concentration. From here, it travels in the bloodstream and binds to receptors. As a hydrophilic molecules, these receptors are found on the cell membrane of both fat and muscle cells.
Binding of this peptide hormone to its receptor results in an intracellular signalling cascade that triggers the recruitment of GLUT4 glucose transport proteins to the cell membrane of fat and muscle cells.
Binding of insulin to its receptor causes a conformational change that triggers phosphorylation of the receptor.
This starts a phosphorylation cascade inside the cell - this is shown in the diagram opposite with 2 different kinase pathways being activated.
A consequence of this phosphorylation cascade is that vesicles, containing GLUT4 transport protein, are transported to the membrane. This will increase in the passive transport of glucose from the bloodstream into the cell.
In the absence of insulin
In the absence of insulin, the insulin receptor remains in a set conformation. It remains unphosphorylated and no downstream, intracellular events are triggered. Glucose remains in the bloodstream.
In the presence of insulin
Insulin binds to its specific receptor on the cell membrane of fat and muscle cells. The receptor undergoes a conformation change, is phosphorylated and triggers a signal transduction cascade. This leads to the recruitment of GLUT4-containing vesicles to the cell membrane. The vesicles fuse with the membrane, allowing the GLUT4 transporters to become incorporated. Glucose is then able to enter the cell, down its concentration gradient.
Diabetes Mellitus
Diabetes mellitus can be caused by:
failure to produce insulin (Type 1)
loss of receptor function (type 2).
Type 2 Diabetes
Type 2 is generally associated with obesity.
However, exercise is a suggested "treatment" route as it triggers recruitment of GLUT4 transport proteins and, therefore, can improve the uptake of glucose to fat and muscle cells in subjects with type 2 diabetes.
Task 64
With so many hopeful medics in the room, Dr McRobbie decided to consider the Glucose Tolerance test next. She explained that the GTT is a blood test that is used to diagnose diabetes. She said, "It measures your body's ability to maintain a normal blood glucose level. For the GTT, a patient is advised to eat normally until the night before the test. They should then not eat or drink anything other than plain water from 10pm the evening before the test".
"Ooft, I'm no going in for that test Miss. I'd be pure scunnered with the hunger", announced Big Davie, and wee Jonny nodded frantically beside him.
Dr McRobbie continued, "upon arriving at the surgery, the patient's blood will be taken before being given a very sweet-tasting, glucose drink. Further blood samples are then taken at regular intervals".
"Ye think it might be Irn Bru ye get...Hmm, nae too bad after all," said Big Davie.
Using information presented in the two figures, can you explain the results observed for the "Normal", "impaired" and "Type 2 Diabetes" patient.
Suggested answers available here.
Now go to SCHOLAR "4.3 Hydrophilic signals and transduction" for consolidation and to try the interactive animation on G-proteins.
Click here for a Quizlet on Topic 1, Key Area 3 and 4.
Time for some Retrieval Practice. On a blank sheet of paper, complete a brain dump on everything you can remember about Communication from KA4a, b and c. Don't open your notes - just write down everything you can remember.
When you have finished, go back through the key area and add in points you have missed in a different pen. File your "brain dump" in with your course notes.
