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Homeostasis, derived from the Greek words home meaning similar and stasis meaning stable (1), is a dynamic state of equilibrium in which the internal and external environments of the body are maintained (2). The maintenance of homeostasis is the most important aspect of the human body. The roots of homeostatic control lay with cellular functions which provide vital products and outcomes directly influencing homeostasis. Following on from the cellular level, there are a multitude of key physiological processes and biochemical products which must be effectively controlled such as blood glucose levels, the pH of the blood, the core body temperature, oxygen saturation, heart rate and electrolyte balance. In order to maintain these, the body has specific countermeasures to prevent an imbalance, which are in the form of negative feedback systems, which work to counteract the change to return the state of imbalance to the optimal conditions. For example, erythropoiesis works to increase the erythrocyte count when its levels are too low. There are a few positive feedback systems which work alongside negative feedback systems to maintain homeostasis, for example the blood clotting process which aims to prevent mass leakage from the development of a thrombus in blood vessels. A homeostatic imbalance would have devastating effects on someones health ranging from total organ failure to strokes and myocardial infarctions. This essay will explain some important cellular functions and how they control the regulation of some of the principles of homeostasis, as well as explaining how a miniscule change in one specific cellular mechanism can result in a severe epidemiological outcome.
Protein synthesis is a major cellular mechanism for homeostatic control within the body, specifically in relation to the regulation of blood glucose levels. Protein synthesis is a complex process whereby DNA strands are translated into mRNA strands and these strands are translated at ribosomes embedded within the rough endoplasmic reticulum (RER). From this point, the recently assembled proteins are transported along the cytoskeleton in a secretory vesicle to the Golgi Apparatus (GA) where they are structurally modified, establishing the function of the protein, be it an enzyme or hormone. This process occurs in the cells of the Islets of Langerhans and influences the proportion of glucose in the extracellular fluid. Upon the detection of hypoglycaemia, ±-cells secrete the hormone glucagon. Therefore, glycogenolysis occurs in the liver and the blood glucose levels increase. Muscular glycogenolysis also occurs and the glucose stores in the muscle are approximately equal to those in the liver. However, muscular glycogenolysis is said to indirectly contribute to blood glucose homeostasis due to the absence of the enzymes required to dephosphorylate glucose. Instead, the glucose is deoxidised into pyruvic acid, which enters the blood stream and is reconverted into glucose by the liver anyway. (2) Adjacent to the ±-cells are the ²-cells secreting insulin whenever hyperglycaemia is detected. In this case, glycogenesis occurs, and the blood glucose levels decrease. The homeostasis of blood glucose levels is regulated through the secretion of these hormones however, it can also be regulated by receptor expression.
Cell surface receptor expression is a crucial part of cellular functioning. The receptor proteins are synthesised and modified throughout protein synthesis; the receptors are glycoproteins expressed in the extracellular membrane, known as the glycocalyx (GCX). Direct evidence was provided in 1966 by Rambourg et al (3) stating that cells are covered by a GCX using a silver methenamine labelling technique to detect glycoproteins in the extracellular membranes of rat tissues. Receptors are directly responsible for the transduction of energy from both internal and external environments into electrical impulses (4). Focussing on the receptors expressed on the post-synaptic membrane of a neuron, it is possible to visualise the effect of receptor function on homeostatic regulation. The membranous receptors are structurally specific to the shape of the neurotransmitter with which it will bind once the neurotransmitters have diffused across the synaptic cleft. Without the specific receptors expressed on the post-synaptic membrane, the electrical impulse will not be re-established (due to cell signalling) and the response to the stimulus will not be carried out. This would have detrimental effects on thermoregulation, such as hypothermia which when detected by the thermoregulatory centre in the hypothalamus is mitigated in response. The sympathetic nervous system will regulate cellular metabolism by inducing the expression of transcriptional regulators of metabolic genes. Therefore, efferent autonomic pathways provide a link between cellular metabolism and thermoregulation (5). Through the manipulation of cellular metabolism, the core body temperature can be raised by increasing the rate of exothermic processes, thus releasing heat. Sympathetically mediated vasoconstriction also occurs in the skin as a thermoregulatory response to minimise heat loss (5), as well as stimulating the rapid contraction of smooth muscle cells (also known as shivering) to aid in the build-up of heat. The same is true for hyperthermia, vasodilation occurs near the surface of the skin and the sympathetic nervous system stimulates the production of sweat, thus reducing the core body temperature. If the receptors were not expressed in the GCX of the post-synaptic membrane of neurons, the electrical impulse would not have been re-initiated, and thermoregulation would not have been successful.
One example of homeostatic impairment arises from protein misfolding. Most newly synthesised proteins fold in their most appropriate minimal-energy configuration, thus ensuring the protein is in its most stable structural configuration. This folding process is a matter of decreasing entropy. The highly disordered DNA strands form amino acids which then enter their unfolded state, then their folding intermediate and finally, their highly ordered native state. Most proteins follow this one pathway but there are many bifurcating pathways which allow variation in their optimal structures. The most prominent structural occurrence of a functional protein in its native conformational state is the ±-helix (6). However, as Reynaud. E describes, when the toxicity increases due to the build-up of amyloid, the conformational shape changes to a ²-pleated sheet and this change promotes protein aggregation due to the exposure of amino acid residues. This one misfolded protein can then induce a toxic state upon other proteins through a process known as infective conformation. This amplification of toxicity eventually either kills the cell or impairs its functional ability. Usually, the cells have a mechanism for detecting misfolded proteins, however, this can become impaired due to the toxicity levels (7). As a result of this, many misfolded proteins bypass this mechanism undetected, therefore diseases can develop, one of which is sickle-cell anaemia.
The NHS describes sickle cell disease as an inherited health conditions that affect red blood cells, the most serious being sickle cell anaemia (8). In this disease, there is an abnormal form of haemoglobin, haemoglobin S (HbS), produced from a mutation in just one of the amino acids in the ²-chains of the globin molecule. This causes the ²-chains to link together, forming stiff rods so that the haemoglobin molecules become sharp and spiky (2), in other words, the unidirectional haemoglobin crystals form these spikes which deform the cell (9). This causes the erythrocytes to form crescent shapes which minimises the volume of oxygen that can be carried by the erythrocyte, thus the cells that require oxygen for aerobic processes are not receiving sufficient volumes of oxygen. Therefore, a state of anaemic hypoxia ensues (10).
There are many symptoms of hypoxia, of which the most common are a rapid heart rate as a result of the increased distribution of oxygen-carrying sickled erythrocytes, an increase in the breathing rate due to an increased need for oxygen, dizziness due to a lack of oxygen to the head and more severe consequences such as strokes and myocardial infarctions due to a lack of oxygen-rich blood being delivered to the heart and brain. Another disease associated with sickle cell anaemia is atherosclerosis. The NHS defines atherosclerosis as a potentially serious condition where arteries become clogged with fatty substances called plaques or atheroma (8). The deformed erythrocytes (containing the sickled haemoglobin) agglutinate and stick to the walls of blood vessels, which contributes to the development of atherosclerotic plaques and eventually blood clots (11). These atherosclerotic plaques partially (or completely in severe scenarios) obstruct the blood flow in vessels, thus minimising the volume of oxygenated blood delivered to necessary cells and organs. Atherosclerosis has similar consequences to hypoxia because both decrease the volume of oxygen being distributed. Therefore, there is an increased chance of strokes and myocardial infarctions as well as increasing the risk of angina and coronary artery disease.
To conclude, the sources of all homeostatic imbalances can be traced back to the cellular level, where a precise component of a cellular mechanism is altered, via a mutation or other means. This, in turn, has detrimental effects on the cellular process which affects homeostatic control, therefore the principles of homeostasis are impeded, and severe consequences tend to follow.
Bibliography
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- Rambourg A, Neutra M, Leblond CP. Presence of a cell coat rich in carbohydrate at the surface of cells in the rat. Anatomic Records 1966. [cited 12th October 2020]
- Thomas L. Lentz, Peter B.C. Matthews. Human nervous system. Encyclopaedia Britannica. 9th April 2020. https://www.britannica.com/science/human-nervous-system [accessed on 15th October 2020]
- Frank Seebacher, Responses to temperature variation: integration of thermoregulation and metabolism in vertebrates. Journal of Experimental Biology. 2009. [cited 15th October 2020]
- Pauling, L. Corey, Rr.b. & Branson, H.R. The structure of proteins: Two hydrogen-bonded helical configurations of the polypeptide chain. PNAS 37, 205-211. 1951. [cited 17th October 2020]
- Reynaud, E. Protein Misfolding and Degenerative Diseases. Nature Education 3(9):28. 2010. [cited 17th October 2020]
- Unknown author. Sickle cell disease. NHS. https://www.nhs.uk/conditions/sickle-cell-disease/ [accessed 17th October 2020]
- Floricin, Stotz. Comprehensive Bio-chemistry. 19B/II. Protein Metabolism. Elsevier Biomedical Press. 1982. [cited 17th October 2020]
- Unknown author. 4 Types of Hypoxia [Effects, Treatment & Prevention]. World of Medical Saviours. https://worldofmedicalsaviours.com/types-of-hypoxia/ [accessed 17th October]
- Unknown author. Sickle Cell Disease and Anemia. The National Institute of Diabetes and Digestive and Kidney Diseases. https://www.niddk.nih.gov/about-niddk/70th-anniversary/sickle-cell-anemia [accessed 17th October 2020]
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