Targets and Receptors for Conditions of the Endocrine System

Question: Write about theTargets and Receptors for Conditions of the Endocrine System. Answer: Introduction Receptors which are located on both the surface of the cell and also with it are the molecular targets through which drugs exert their effects in various diseases and health conditions. The term 'receptor' is used in a broader sense to refer to any recognition site for drug and drug-like compounds. They are defined as per their selectivity, saturability, functionality, and reversibility of ligand binding (Williams, 2006). Defining a receptor in both physiological and pharmacological terms means that it bears precise interactions with ligands belonging to a particular pharmacological class. Thus, drug compounds used in the treatment of conditions of the endocrine system need to have a specific compound structure to be able to target the various receptors for the delivery of therapeutic effects. This paper is a discussion on the targets and receptors in the treatment of the various conditions of the endocrine system. This discussion is carried as per each individual condition or where feasible, class of conditions, outlining the drug compounds used and their targets. Discussion There are different classes of drugs adopted for the treatment of the various presentations of disorders of the endocrine system. It is, therefore, necessary to group and classify these disorders. There are four primary classes of disorders relevant to this discussion; disorders in glucose homeostasis. thyroid disorders, disorders in calcium homeostasis, and disorders of pituitary gland. Targets and receptors in the treatment of glucose homeostasis disorders Conditions classified under glucose homeostasis disorders include diabetes, hypoglycemia, and glucagonoma. The glucagon receptor (Gcgr) The glucagon receptor is a peptide hormone mainly expressed in the liver and kidney with other minor sources such as the heart, spleen, GI tract, pancreas, adipose tissue, thymus, adrenal glands, and cerebral cortex. This receptor is one of the members in the family B receptors classified under the G protein-coupled super-family of 7 transmembrane-spanning receptors (Authier Desbuquois, 2008) Glucagon is the primary hormone which opposes the action of insulin. It is the primary hormone secreted by pancreatic alpha cells whose primary role is the provision of sustainable supply of glucose to the vital organs during fasting periods. To achieve this, hepatic glucose production is stimulated by specific G-protein-coupled receptors (GPCRs) located mainly hepatocytes (Christensen, et al., 2011). Patients presenting with type 2 diabetes mellitus, have elevated levels of glucagon which plays a key function in the development of hyperglycemia among this group of patients. Evidence from a number of research studies shows that targeting the pancreatic alpha-cells and glucagon (its primary secretory product) can T2DM(Christensen, et al., 2011). With such evidence, drugs developed in the management of T2DM either antagonise the glucagon receptor or suppress glucagon secretion. Glucagon receptor (GCGR) antagonism in the management of hyperglycaemia has been demonstrated using glucagon peptide antagonists, small molecular weight GCGR antagonists, GCGR antisense oligonucleotides, and anti-glucagon neutralising antibodies can treat diabetes (Sloop, 2005). The insulin receptor(IR) This is a transmembrane receptor belonging to the class of tyrosine kinase receptors. Its activation is mediated by insulin, insulin-like growth factor 1 (IGF-1), and insulin-like growth factor 2 (IGF-2) (Ward Lawrence, 2009). This receptor regulates glucose homeostasis. Drugs targeting the insulin receptor increases the affinity of glucose transporter molecules on tissues that are insulin-responsive, and as a result increases the uptake of blood into such tissues (Boucher, et al., 2014). Glucagon-like peptide 1 receptor (GLP1R) This receptor is found in pancreatic beta cells and its activation leads to the stimulation of the adenylyl cyclase pathway which translates to increased insulin synthesis and its release (Holst, 2004). This receptor has been a target in the development of the class of drugs known as GLP1R agonists used in the treatment of diabetes. GLP1R agonists potentiate the glucose-induced secretion of insulin from pancreatic beta cells, suppresses post-prandial glucagon release, promotes beta-cell neogenesis and also inhibits their apoptosis, delays stomach emptying, increases expression of insulin, elevates peripheral glucose disposal and promotes satiety (Donnelly, 2012). Free fatty acid receptors Free fatty acids (FFAs) play a significant role in glycaemic regulation and the pathogenesis of T2DM (Bergman Ader, 2000). GPCRs for FFAs form part of the body's nutrient sensing mechanism and are included in the pancreas, GI tract, leucocytes, adipose tissue and other parts of the CNS. This class of receptors are not restricted to the lock and key theory but are rather considered to be diverse in the sense that their activation is mediated by a wide range of ligands (Vangaveti, et al., 2010). Vangaveti and fellow authors further claim that agonists of FFAR1 and GPR119 (long-chain FFA receptors) serve as insulin secretagogues, both directly and by also increases incretins which in turn stimulates a decline in blood glucose levels. Activation of GPR119 reduces food intake, causes a reduction in body weight gain, regulates incretin and hormone secretion (Lan, et al., 2009). This demonstrates that drugs that exert their function through this receptor can treat both diabetes and obesity (Overton, et al., 2008). Somatostatin receptors Somatostatin receptors are members of the G protein-coupled seven transmembrane receptors (Bronstein-Sitton, 2006). They are targets for somatostatin analogues such as octreotide used in the treatment of glucagonoma. Activation of these receptors signals for the secretion of IGF-1 and also decreases the secretion of glucagon. Targets and receptors in the treatment of thyroid disorders The most prevalent disorders of the thyroid gland include goitre, hypothyroidism, hyperthyroidism, thyroiditis, thyroid hormone resistance, toxic multinodular goitre, thyroid cancer, and Graves-Basedow disease. Thyroid disorders may result due to either iodine deficiency, autoimmunity, genetic factors or environmental factors (Simmonds Gough, 2005; Weetman, 2003). However, autoimmunity is the most prevalent cause. Problems such as hypothyroidism characterised by the inadequate production of thyroxine hormone by the thyroid gland require thyroxine therapy. The receptors for the thyroxine from drugs such as Levothyroxine (LT4) are the thyroid hormone receptor (TR) (alpha-1, beta-1, and beta-2) which are a type of nuclear receptor. Nuclear receptors are types of proteins found in cells with the responsibility of sensing steroid and thyroid hormones (Olefsky, 2001). Thyroid hormone receptors function as hormone-activated transcription factors, and as such, they act by modulating gene expression. Thyroid hormone receptors bind to DNA causing functioning as a transcriptional activator (Zhang Lazer, 2000). This action, however, needs to be down-regulated in the event of hyperthyroidism. In hyperthyroidism, the thyroid gland produces an excess of the hormone thyroxine. Its treatment includes anti-thyroid pharmacotherapy, radioactive iodine-131 therapy, and thyroidectomy (Lee, 2017). Agents for anti-thyroid pharmacotherapy such as Propylthiouracil act by inhibiting the peripheral conversion of thyroxine to tri-iodothyronine (Lee, 2017). The receptors for this therapy are the thyrotropin receptors or thyroid stimulating hormone (TSH) receptors. Thyrotropin receptors are also included in the GPCR group (Farid Szkudlinski, 2004). Thyroid stimulating receptors are found on the surface of thyroid epithelial cells, adipose tissue, and fibroblasts. The mode of function of thyrotropin receptors is that they bind circulating TSH and this signals a G-protein signal cascade which leads to the activation of adenylyl cyclase and also increases the intercellular levels of cyclic adenosine monophosphate (cAMP) (Goel, et al., 2013). The latter activates all functional mechanisms of thyroid cells which include iodine pumping, iodination, endocytosis, proteolysis and the synthesis of thyroglobulin and as a result reduce the amount of thyroxine available (Sellitti Suzuki, 2014; Hashizume, et al., n.d.). Targets and receptors in the treatment of thyroid calcium homeostasis disorders This class of disorders includes parathyroid gland disorders (hyperparathyroidism and hypoparathyroidism), osteoporosis, rickets and Pagets disease of bone. Hyperparathyroidism is treated using calcimimetics whose mode of action is to mimic the action of calcium on tissues. It mimics calcium at the parathyroid hormone receptor leading to a binding that improves the sensitivity of calcium-sensing receptors (CaSR) on the parathyroid gland (Riccardi Martin, 2008). CaSR is also a Class C GPCR predominantly found in the parathyroid gland and some on the renal tubules of the kidney. There two forms of the parathyroid hormone receptors (parathyroid hormone 1 receptor (PTH1R) and parathyroid hormone 2 receptor (PTH2R) which are also members of GPCRs whose main function is regulation of calcium ion homeostasis (Pioszak Xu, 2008). Bisphosphonates are also used in the treatment of the osteoporosis, loss of bone mass and other similar diseases (National Osteoporosis Society, 2012). The target for this class of drugs is the bone tissue where they are ingested by osteoclasts. Targets and receptors in the treatment of pituitary gland disorders Some of the disorders in this group include diabetes insipidus, hypopituitarism, and pituitary tumours. Diabetes insipidus results from the lack of anti-diuretic hormone (ADH), and its treatment involves the use of a synthetic hormone called desmopressin. The target receptors for desmopressin is the vasopressin receptors (V1, V2, and V3), more precisely the V2 receptors (Robben, et al., 2004). The V2 receptor is also a GPCR which regulates homeostasis of water, glucose and salts in the blood. These receptors are predominantly located in cell membranes of the distal convoluted tubule and collecting ducts Conclusion Targets and receptors for drugs used in the treatment of conditions of the endocrine system are diverse and they are dependent on the function of the endocrine organ impaired. Even in cases involving the same hormone but differently classified into either hyper-production or hypo-production, the target receptors are also different. References Authier, F. Desbuquois, B., 2008. Glucagon receptors. Cell. Mol. Life Sci, 65(1881), pp. 1880-1889. Bergman, R. Ader, M., 2000. 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