Glucagon and cAMP Metabolism Modulation - Lab Report Example

? Glucagon and cAMP Metabolism Modulation GLUCAGON AND cAMP METABOLISM MODULATION Overview Glucagon and cyclic adenosine monophosphate are first and second messengers in the pathways that lead to a rise in glucose levels of blood. Glucagon is produced in the pancreas as a peptide hormone and has an effect on blood glucose that is opposite to the effect of insulin1. While insulin is released to lower levels of blood glucose, glucagon does the opposite and is released when there is a significant or dramatic drop in levels of glucose. When it is released, it acts on the liver, which in turn releases glucose into the blood that was previously stored as glycogen. When these glucose levels reach a high level, the pancreas will release insulin that stimulates tissues that are dependent on insulin to take up the excess glucose. Therefore, glucagon is one part of the feedback system, together with insulin, that stabilizes the levels of blood sugar. Glucagon is synthesized in the islets of langerhans by the alpha cells and secreted by the same cells. The islets of langerhans are found in the pancreas’ endocrinal portion and in man1. Glucagon is a peptide hormone with 29 amino acids, and generally, it acts to raise sugar levels present in the blood through promotion of glycogenolysis and gluconeogenesis, which refer to splitting of stored glycogen to glucose sub-units and formation of glucose respectively2. It exists as an inert holoenzyme, pro-glucagon, which is activated by pro-hormone convertase into glucagon. Glycogen is a polymer form of glucose that is similar to starch in plants and is stored in liver hepatocytes. These hepatocytes possess receptors for glucagon that bind the hormone. On binding of glucagon, the hepatocytes release glucose from the glycogen polymer released to the blood, for use by other cells through glycogenolysis. Simultaneously, glucagon also binds to hepatocytes and kidney cells and stimulates the synthesis of glucose through the process of gluconeogenesis. Through, shutting down the process of glycolysis, glucagon leads to the shunting of glycolytic intermediates to the reformation of glucose. The hormone also has a minimal on the human process of lipolysis. It appears that production of glucagon depends on the CNS, although the pathways that affect the production of glucagon are yet to be clearly defined. Glucagon dissociates soon after it binds onto the glucagon receptors since they change the configuration after activating cyclic adenosine monophosphate2. The free glucagon is dissociated in the blood by proteolytic enzymes. Cyclic adenosine monophosphate is a nucleoside phosphate, which acts as a second messenger and is of utmost importance in numerous processes in the human body. The messenger is formed from ATP, and the resultant molecule is used in signal transduction within the cell acting in the cyclic adenosine monophosphate dependent pathway3. Adenylate cyclase, which is found on the inner membrane’s inner surface, synthesizes cyclic adenosine monophosphate from the precursor molecule ATP. Adenylate cyclase enzyme undergoes activation through G-protein coupled receptors, whereas it is inhibited by inhibitory G-protein coupled receptors. Adenylate cyclase within the liver and in the muscles is more specific to glucagon than it is to adrenalin3. Cyclic adenosine monophosphate has one phosphate group that is bound to position three and position five of the sugar through two phosphate-ester linkages4. These linkages form a cyclic structure or a ring that is limited by residues of oxygen and phosphorous, as well as by the carbons at position three and five. This explains why it is referred to as cyclic adenosine monophosphate. It is used for signal transductions within human cells for passing on the effects of hormones that cannot pass through the plasma membrane, such as the peptide hormone glucagon. Cyclic adenosine monophosphate is particularly involved in protein kinase activation. It also binds to ion channels and regulates their permeability. Some of these ion channels include HCN channels, calcium channels, and potassium channels. It also binds and regulates some cyclic nucleotide-binding proteins like RAPGEF2 and Epac14. Cyclic adenosine monophosphate, which is a second messenger, is decomposed by phosphodiesterase to AMP after its activity. Cyclic adenosine monophosphate has three major targets within the cell, including cyclic-nucleotide-gated ion channels, EPAC protein, and protein kinase A5. Protein kinase A is involved in the interference of various signaling pathways at various levels. Some examples include phospholipase C inactivation, tyrosine phosphatase phosphorylation, modulation of permeability in ion channels, and down-regulation of activity in Rho and Raf. Cyclic adenosine monophosphate also binds to cyclic-nucleotide-gated ion channels and modulates their function, particularly the action channels, which are non-selective. By modulating potassium and sodium, cyclic adenosine monophosphate, is involved in the alteration of membrane potential in cells that are electrically active. Finally, the messenger also modulates MAPK or mitogen-activated protein kinase pathway through activation of EPAC, which is a GTP exchange protein for GTPase Rap15. Biochemical Pathways Various first messengers provoke the formation of cyclic adenosine monophosphate within the cells. In this case, the first messenger under study is glucagon. Glucagon leads to cyclic adenosine monophosphate formation through adenylate cyclase mechanism, which is coupled to G-protein6. Cyclic adenosine monophosphate is formed after ATP is split to AMP and made cyclic by adenyl cyclase, which is a trans-membrane protein with the domain on the cytoplasmic side being the active domain. The mechanism through which glucagon amplifies the concentration of intracellular cyclic adenosine monophosphate is first achieved through the binding of glucagon to the G-protein coupled receptors on the surface of liver, muscle, and kidney cells. These G proteins are Guanine nucleotide binding proteins, and they are to be found on the plasma membrane’s cytoplasmatic side. These Guanine nucleotides have three sub-units including gamma, beta, and alpha sub-units. The alpha sub-units have four families with an individual sub-unit being responsible for various intracellular responses because it has specificity for a particular effector protein6. The G?s is the alpha sub-unit that has specificity for adenyl cyclase, and it is contained within the Gs protein. The glucagon and glucagon receptor interaction lead to the activation of the Gs protein because the binding of glucagon leads to the process through which hormones utilize the mechanism involving the G-protein7. It involves interchanging the alpha unit-bound GDP with GTP, activation of the specific effector protein by the complex of GTP and alpha subunit, and dissociation of the complex between GTP and the alpha sub-unit. Because of the association between the glucagon receptor and the Gs protein, the complex of GTP- G?s is bound to the adenyl cyclase, which, in turn, provokes the formation of cyclic adenosine monophosphate7. The cyclic adenosine monophosphate operates via the activation of PKA, or protein kinase A, in humans. The protein Kinase A is cyclic adenosine monophosphate-dependent and is usually not active, existing as a tetrameric holoenzyme that has two units for regulation and two units that are catalytic in nature8. The regulatory units usually act to block the catalytic subunit centers. Cyclic adenosine monophosphate is bound to particular regulatory unit locations on the PKA, leading to the occurrence of dissociation between the catalytic and regulatory subunits. This leads to the catalytic units being activated, which, in turn, enables substrate proteins to be phosphorylated through the activity of the catalytic units8. The active catalytic subunits catalyze the removal of phosphate from a molecule of ATP to a specific residue on the protein substrate that can be either threonine or serine. This resultant enzyme activates the enzyme phosphorylase kinase that phosphorylates another enzyme glycogen phosphorylase9. Phosphorylation of glycogen phosphorylase leads to the formation of phosphorylase A that is responsible for phosphorylation of glycogen polymers to produce glucose-1-phosphate. This is referred to as an enzymatic cascade, where the first messenger, in this case glucagon, leads to amplification of activity of enzymes and co-factors within the cell. The result of this biochemical pathway is the increase in glycogenolytic activity, a simultaneous decrease in glycogenolysis or formation of glycogen, increased levels of glucose formation through gluconeogenesis, increased ketogenesis due to gluconeogenesis, and increased mobilization of fatty acids in the adipose tissue9. This last effect is not very sensitive to glucagon in humans, however. Disease States Increased level of glucagon in the body, also referred to as hyper-glucagonemia is caused by various factors. Those tumors associated with glucagonoma are able to spread across the body and are normally malignant. These tumorous alpha cells in the pancreas lead to excessive secretion of glucagon, which may result in hyper-glucagonemia10. Glucagonoma risks are also increased, by a pre-disposition, to endocrine gland tumors, such as multiple endocrine neoplasias. Diseases like diabetes mellitus and pancreatic illnesses like pancreatitis also lead to increased levels of glucagon in the blood. In addition, liver cirrhosis, kidney failure, Cushing Syndrome that raises cortisol levels, myocardial infarction, and septicemia also result in hyper-glucagonemia. This is a state of excessive levels of glucagon in the blood and can be caused by lack of the suppressive effect of insulin, on secretion of glucagon through interference with the function of pancreatic alpha cells10. While this condition is not common, it leads to very high levels of glucagon in the blood. Low glucagon levels in the blood may lead to hypoglycemia, which is a strong stimulant for the secretion of glucagon. If glucagon is not produced due to a range of factors, hypoglycemia increases without being checked. If physiologic secretion of insulin does not occur, hypoglycemia cannot correct hypoglycemia11. Therefore, the factors that lead to decreased insulin production also lead to inactivity of glucagon, even if it is being produced. In addition, an inability to produce glucagon by the alpha cells in the pancreas leads to chronic hypoglycemia. This condition is caused by various factors including defective release from the liver of glucose, beta cell tumors, Addison’s disease that causes decreased corticosteroid levels that should enhance production of glucose, as well as decreased growth hormone secretion11. Low glucagon secretion leads to increased hypoglycemia and eventual loss of consciousness due to low levels of glucose available for the brain. Low glucagon levels also lead to seizures and death in people who suffer from diabetes. With regards to cyclic adenosine monophosphate, it is of utmost importance in the regulation of various physiological processes. For this reason, it is not surprising that a number of disorders and diseases that result from its improper regulation exist. For instance, activated Gsa mutants cause Mc-Cune Albright Syndrome, as well as benign neoplasia where cells with increased cyclic adenosine monophosphate are mitogenic12. This leads to elevated and autonomous cyclic adenosine monophosphate production that causes hyper-function and hyperplasia. This has an adverse effect on many endocrine glands like the pituitary somatrophs, thyroid, adrenal cortex, and gonads. Where there are abnormalities in cyclic adenosine monophosphate dependent systems of phosphorylation, bi-polar disorder could occur. This is because there is an alteration in catalytic subunits of cAMP-dependent PKA and Rap1 levels in platelets of people suffering from bipolar disorder13. Low cAMP levels also lead to similar problems as those faced when one has low levels of glucagon such as hypoglycemia. Remediation Hyper-glucagonemia, or high glucagon levels, can be treated using octreotide, which is a therapeutic agent. It can be used together with embolization of the hepatic artery and chemotherapy in the case of pancreatic tumors that cause over-production of glucagon14. It has a three-hour half-life and is used for the de-bulking of metastatic tumors. It also blocks the production of glucagon, as well as its effects. Because of its short half-life, it is used, after meals, to stop production of glucagon when the blood already has enough glucose from the meal. Treatment of cell tumors in the islets of langerhans also treats hyper-glucagonemia. This is through the combination of chemotherapy with 5-flourouracil and streptozocin that leads to tumor shrinkage. Interferon, cyclophosphamide, lomustine, etoposide, cisplatin, and dacarbazine are also used in combination. Forskolin, extracted from the Indian Coleus plant is used to increase cyclic adenosine monophosphate levels, whereas also increasing the sensitivity of cell receptors through the activation adenyl cyclase, which, in turn, increases cyclic adenosine monophosphate15. In cases where there is overproduction of cAMP, bi-guanides can be used since they increase AMP concentration, inhibiting adenylate cyclase, which, in turn, reduces production of cAMP. References 1. Voet D, Judith GV. Biochemistry. Hoboken, NJ: John Wiley & Sons, 2011 2. Coffee CJ. Metabolism: Raleigh, NC: Hayes Barton Press, 2004 3. Murray R. Cyclic-AMP-Dependent Protein Kinase: New York: MSS Information Corp, 2007. 4. Taylor, CM. Intracellular Messengers. Amsterdam: Elsevier Science, 2009 5. Goodman HM. Basic Medical Endocrinology: Amsterdam: Elsevier/Academic Press, 2009 6. Beckerman M. Molecular and Cellular Signaling: New York: Springer, 2005. 7. Lieberman M, Allan DM, Alisa P. Marks' Basic Medical Biochemistry: A Clinical Approach. Philadelphia: Wolter Kluwer Health/Lippincott Williams & Wilkins, 2013 8. Robison G. Cyclic AMP. Oxford: Elsevier Science, 2011 9. Bittar EE, Neville B. Membranes and Cell Signaling: Greenwich, Conn: JAI Press, 2007 10. Lefe?bvre PJ. Glucagon. Berlin: Springer-Verlag, 2009. 11. Islam S. The Islets of Langerhans: Dordrecht: Springer, 2009 12. Rastogi SC. Biochemistry. New Delhi: Tata McGraw-Hill Education, 2010 13. Riedel G, Bettina P. From Messengers to Molecules: Memories Are Made of These. Georgetown: Tex, 2004 14. Frayn KN. Metabolic Regulation: A Human Perspective. Chichester: John Wiley & Sons, 2010 15. Fernandez J. Inborn Metabolic Diseases Diagnosis and Treatment: Heidelberg: Springer, 2006. Read More