BIOL1121 UNIT5 Written Assignment: Paracrine Signalling of Glutamatergic Synapse and Effect of Endocrine Disruptors

As discussed in your text book, there are four categories of chemical signalling found in multicellular organisms; paracrine signalling, endocrine signalling, autocrine signalling and direct signalling across gap junctions. For this written assignment you will choose one of these signalling pathways to investigate in more detail.

• Choose one out of paracrine signalling, endocrine signalling, autocrine signalling and direct signalling and describe briefly the process by which this occurs.
• Pick a representative signal molecule from the pathway you have chosen and indicate its function, the type of cell in which it is made and the specific manner in which it acts as a signalling molecule, including the receptor that it binds to.

For example if you chose the endocrine signalling pathway you could consider looking at a hormone such as insulin.  You would describe the cells from which insulin is secreted and state the overall role of insulin in the body.  In signalling pathways, each signal molecule has a receptor that it binds to, so you would indicate what the receptor for insulin is called and what immediate outcome the binding of insulin has to that receptor i.e. in the case of insulin, which regulates glucose uptake in the body, does the receptor directly interact with glucose or is it just part of a much larger signalling cascade.

KEGG PATHWAY Database

To give you an indication of the complexity of cell signalling, visit the KEGG (Kyoto Encyclopaedia of Genes and Genomes) PATHWAY database.  This database maps biological pathways and displays them as a collection of diagrams or graphs.  If you wish to read more about it visit the overview page of the database.

• Open the KEGG PATHWAY Database homepage. On this page, you can browse various types of pathways, including metabolic and signalling pathways or you can search for terms and find the associated pathways.
• Using the search box, search for the molecule you have discussed above by entering its name.
• KEGG may give you the choice between several pathways, choose one of these and click on the link under the heading ‘entry’. (this will read something like map01578)
• Read the description of the pathway and write down its name then click on the image of the map.
• If possible copy the image of the map and insert it into your written assignment, if this does not work for you provide a URL so that the page can easily be accessed. The map consists of a set of rectangles and circles which represent molecules, connected by lines which indicate how these molecules interact or relate with each other.  To understand how the information is organized on the map, click on the "Help" button at the top left of the screen. You can explore the map by clicking on its individual elements and investigate the kinds of information is available.
• Try to identify your chosen molecule on the map and make a note of the number and names of other molecules it directly interacts with in this pathway. If you are unable to identify your molecule of choice see if you can find its receptor, which you identified earlier in this assignment.
• Click on the shape that contains your molecule of interest (or its receptor) (this will redirect you to a page that lists the signalling pathways in which that molecule is involved and any diseases associated with it)
• Take a note of the names of at least three other pathways indicated on this page and comment on whether your molecule is linked with any diseases. (If there is no disease association there will be no entry in the table)
• Review Endocrine Disruptors and provide a brief overview of the mechanism of action of endocrine disruptors. Comment on some of the effects of known endocrine disruptors and suggest some steps that can be taken to reduce the dangerous health effects posed by chemicals of this nature

Written Assignment Requirements

Your written assignment should be submitted in a Word document (or similar program), double-spaced with 1-inch margins, and written in Times New Roman size 12 font.  You should provide a word count at the end of your written assignment.  Remember to include APA formatted citations for all of the information you have provided.

 

Written Assignment Peer Assessment

In the unit following the submission of your written assignment, you will peer assess three (3) of your classmates’ assignments according to the instructions found in the Assessment Form. During this peer assessment period, you are expected to provide details in the feedback section of the Assessment Form, indicating why you awarded the grade that you did to your peer. The written assignment grade is comprised of a combination of your submission (90%) and your peer assessments (10%).

Written Assignment Peer Assessment Rubric

For this assignment, your peers will be evaluating your work with the following criteria.

• Has the student indicated which type of signalling pathway they are discussing and given a clear description of it? (2 points)
• Has a signalling molecule been chosen that is representative of the pathway described and the function of that molecule defined? (2 points)
• Has the receptor of the signalling molecule been identified? (1 point)
• Has a signalling pathway been identified using the KEGG database? (2 points)
• Has the student identified at least three alternative pathways the molecule is associated with? (1 point)
• Has the concept and mechanism action of endocrine disruptors been reviewed with examples? (2 points)
• Have suggestions been made on how to limit the effects of endocrine disruptors? (2 points)
• Is there commentary on effects of know endocrine disruptors? (1 point)
• Has at least one APA formatted citation been provided, not including the KEGG database? (1 point)
• Is the assignment well organized and easy to read?

 

 

 

 

 

I chose Paracrine Signalling for this written assignment, and I will explain its process and example briefly. Paracrine Signalling acts locally between cells that are close together, and it moves by diffusion through the extracellular matrix (Clark et al., 2020). A cell produces a signal called ligands to induce changes in a nearby cell, changing the cell's actions. Signalling molecules are known as paracrine factors, and the phenomenon which causes changes in neighboring cells in a small distance such as Paracrine Signalling is called paracrine interaction. 

As the textbook explains, an example of paracrine signaling is the transfer of signals across synapses between nerve cells. A nerve cell consists of a cell body, several short branched extensions called dendrites that receive stimuli, and a long extension called an axon, which transmits signals to nerve cells or muscle cells (Clark et al., 2020). At synapses, neurotransmitters are released from the ends of axons, and these neurotransmitters are received by receptors located in the dendrites of the next nerve cell. Glutamate and glutamate receptors play a major role in our brain (Huang & Bergles, 2004).

 

I chose the Glutamatergic synapse from KEGG PATHWAY Database. Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system, and it is packaged into synaptic vesicles in the presynaptic terminal. It acts on postsynaptic ionotropic glutamate receptors to mediate fast excitatory synaptic transmission when released into the synaptic cleft (KEGG PATHWAY., n.d.). 

I chose PKA, protein kinase A [EC:2.7.11.11] from the map. The other molecule it directly interacts with in this pathway is Cyclic adenosine monophosphate (cAMP). Cyclic adenosine monophosphate is made from ADCY1, adenylate cyclase 1 [EC:4.6.1.1] by feedback inhibition of glutamate release (KEGG PATHWAY., n.d.). "Cyclic adenosine monophosphate (cAMP) is a common second messenger that is regulated by the activation of G protein-coupled receptors (GPCRs) and mediates numerous biological responses" (ScienceDirect., n.d.. para.1). Its main action is activating protein phosphorylating enzymes (protein kinases), which are also used to regulate the passage of Ca2 + through ion channels (ScienceDirect., n.d.). Alternative pathways associated with PKA molecules include Ras signalling pathway, calcium signalling pathway, cAMP signalling pathway, chemokine signalling pathway, etc. (KEGG PATHWAY., n.d.). And finally, PKA again becomes glutamate by exocytosis (KEGG PATHWAY., n.d.).

 

 

Glutamatergic synapse Retrieved from https://www.genome.jp/pathway/map04724

 

 

Next, I will describe three diseases linked to the PKA molecules.

1. Cushing syndrome
Cushing syndrome occurs when your body has too much of the hormone cortisol over time. some of the hallmark signs are a fatty hump between your shoulders, a rounded face, and pink or purple stretch marks on your skin; and sometimes it also results in high blood pressure, bone loss, and, on occasion, type 2 diabetes (Mayo Clinic. (n.d). In a survey conducted by Beuschlein et al., PRKACA somatic mutations were identified in 22 of 59 unilateral adenomas (37%) from patients with overt Cushing's syndrome; they found genetic alterations of the catalytic subunit of PKA were found to be associated with human disease (2014).

2. Macrothrombocytopenia
Macrothrombocytopenias are the most important subgroup of inherited thrombocytopenia, and it is a blood disorder characterized by a reduced platelet count in the blood (Manchev et al., 2014). Protein Kinase CAMP-Activated Catalytic Subunit Gamma is a new central actor in platelet biogenesis, and its mutation leads to inherited thrombocytopenia with giant platelets associated with a thrombocytopathy (Manchev et al., 2014).

3. Bilateral macronodular adrenal hyperplasia
Inactivating mutations of the 17q22–24- located PRKAR1A gene, coded for PKA, cause primary pigmented nodular adrenocortical disease, and the Carney complex's multiple endocrine neoplasia syndrome often leads to Cushing syndrome (Bourdeau et al., 2006).

 

 

 

Finally, I will describe Endocrine Disruptors and provide a brief overview of the mechanism of action of endocrine disruptors. 

Many chemicals, both natural and man-made, may mimic or interfere with the body's hormones; it is called Endocrine Disruptors (National Institute of Environmental Health Sciences., n.d.).  Endocrine Disruptors are often included in many everyday products such as plastic bottles and containers, liners of metal food cans, detergents, flame retardants, food, toys, cosmetics, and pesticides; and we take in these chemicals in our bodies through diet, air, skin, and water (National Institute of Environmental Health Sciences., n.d.). 

EDCs such as dioxins, PCBs, PBBs, and pesticides often contain halogen group substitutions by chlorine and bromine; those often mimic natural steroid hormones and enable EDCs to interact with steroid hormone receptors as analogs or antagonists (Diamanti-Kandarakis, et al., 2009). Steroid hormones include corticosteroids, estrogens, testosterone, etc., even infinitesimally low levels of exposure to EDCs may cause endocrine or reproductive abnormalities, particularly if exposure occurs during a critical developmental window (Diamanti-Kandarakis, et al., 2009).

Then, how do we can limit the effects of endocrine disruptors? I think natural endocrine disruptors are suppressed to the extent that the human body can cope. The key is how to reduce the impact of human-produced endocrine disruptors.  It is essential to choose what we touch, eat and drink as much as possible from natural materials to reduce exposure to endocrine disruptors contained in chemical materials. For example, we can select organic food or meat that does not use growth-promoting hormones even if it is more expensive than other merchandise.



References

Beuschlein, F., Fassnacht, M., Assié, G., Calebiro, D., Stratakis, C. A., Osswald, A., ... & Allolio, B. (2014). Constitutive activation of PKA catalytic subunit in adrenal Cushing's syndrome. New England Journal of Medicine, 370(11), 1019-1028. Retrieved from https://www.nejm.org/doi/full/10.1056/NEJMoa1310359

Bourdeau, I., Matyakhina, L., Stergiopoulos, S. G., Sandrini, F., Boikos, S., & Stratakis, C. A. (2006). 17q22–24 chromosomal losses and alterations of protein kinase a subunit expression and activity in adrenocorticotropin-independent macronodular adrenal hyperplasia. The Journal of Clinical Endocrinology & Metabolism, 91(9), 3626-3632. Retrieved from https://academic.oup.com/jcem/article/91/9/3626/2656799?login=true

 

Chen, Q., Liu, A., Qiu, H., & Yang, Y. (2015). Mesenchymal stem cell and endothelial cell interaction restores endothelial permeability via paracrine hepatocyte growth factor in vitro. Critical Care, 19(1), 1-201. Retrieved from https://link.springer.com/article/10.1186/cc14316

Diamanti-Kandarakis, E., Bourguignon, J. P., Giudice, L. C., Hauser, R., Prins, G. S., Soto, A. M., ... & Gore, A. C. (2009). Endocrine-disrupting chemicals: an Endocrine Society scientific statement. Endocrine reviews, 30(4), 293-342. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2726844/

Huang, Y. H., & Bergles, D. E. (2004). Glutamate transporters bring competition to the synapse. Current opinion in neurobiology, 14(3), 346-352. Retrieved from https://www.science.org/doi/10.1126/science.aay4631

KEGG PATHWAY. (n.d.). PATHWAY: Map04724. Retrieved from https://www.genome.jp/dbget-bin/www_bget?pathway:map04724

Manchev, V. T., Hilpert, M., Berrou, E., Elaib, Z., Aouba, A., Boukour, S., ... & Raslova, H. (2014). A new form of macrothrombocytopenia induced by a germ-line mutation in the PRKACG gene. Blood, The Journal of the American Society of Hematology, 124(16), 2554-2563. Retrieved from https://ashpublications.org/blood/article/124/16/2554/33224/A-new-form-of-macrothrombocytopenia-induced-by-a

Mayo Clinic. (n.d). Cushing syndrome. Retrieved from https://www.mayoclinic.org/diseases-conditions/cushing-syndrome/symptoms-causes/syc-20351310

National Institute of Environmental Health Sciences. (n.d.). Endocrine Disruptors. Retrieved from https://www.niehs.nih.gov/health/topics/agents/endocrine/index.cfm

ScienceDirect. (n.d.). Cyclic Adenosine Monophosphate. Retrieved from https://www.sciencedirect.com/topics/neuroscience/cyclic-adenosine-monophosphate