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2 nd stage/2017 Dr. Thana Alswedi / Biochemistry Hormones Any substance released by a cell and acts on another cell, near or far from site of secretion. Biosynthetic mechanisms are many. Some protein hormones are synthesized as precursors,which are converted to active form by removal of certain peptide sequences.E.g. Insulin is synthesized as pre-proinsulin (m.wt11500).Removal of some amino acids,peptides produce insulin (m.wt 5734).Thyroxine, a single amino acid hormone. It is synthesized as a glycoprotein precursor called thyroglobulin, which has 115 amino acids. Other hormones like glucocorticoids/ minerolacorticoids from Adrenal gland are synthesized and secreted in their final active form. Storage Hormones are stored in secretory granules within the cytoplasm of endocrine cells. eg. Thyroid hormones are stored in follicles filled with colloid particles. Catechoamines of Adrenal medulla are stored in secretory granules of cytoplasm. • Storage always protects the molecule from untimely inactivation. • Steroid hormones are not stored in significant quantities. • In response to stimulus they are synthesized and released immediately. Release: • When the target cells require free hormones, they are released immediately. • Protein, polypeptide hormones are released by exocytosis or pinocytosis. It involves fusion of granules and cellular membrane, followed by secretion in to blood stream. 1 • Stimulus excites the endocrine cell. • The specific enzymes in the storage vesicle activate the hormone before release. • Disruption of the process by certain drugs interferes with exocytosis. Transport: • Some hormones are soluble and do not require transport proteins. • Free hormone is the fraction available for binding to receptors and therefore represents the active form. Free Hormone concentration correlates best with the clinical status of either excess or deficit hormone. • Steroid hormones are lipid soluble. They diffuse through cell membrane. • Specific transport proteins are found in blood for carrying steroid hormones and thyroxine. Plasma globulins bind to thyroxine, cortisol and sex hormones. The binding is noncovalent type.Some hormones bind loosely to proteins like albumin for transport. Binding to plasma proteins protect them from inactivating systems. • It also keep the hormones in readily available circulatory form to the target tissues. Hormones and binding proteins Hormone Binding proteins. Thyroxine (T3) Thyroxine binding globulin (TBG), Thyroxine binding Pre-albumin (TBPA). Aldosterone Albumin Estrogen steroid hormone binding globulin (SHBG). 2 Testosterone SHBG and Albumin. Cortisol Cortisol binding globulin (CBG). Control of Hormone Release Most hormone synthesis and release is regulated through negative feedback mechanisms. Nervous system modulation allows hormone secretion to be modified by the nervous stimulation in response to changing body needs. Hormone action and Signal Transduction Cellular functions are regulated by hormones, neurotransmitters and growth factors through their interaction with the receptors, located at the cell surface. Some hormones elicit hormonal cascade system. Based on mechanism of action, the hormones may be classified into two groups: I. Mechanism of action of Protein hormones • The group comprises the peptide/protein hormones. • They can’t enter target cells. • They deliver message to the cell surface receptors. • The receptors are integral glycoproteins with 3 functional domains. A. Extra cellular domain which binds to hormone B. Trans membrane domain penetrates lipid bilayer. C. Intracellular domain coupled with the effector system. * The hormone binds to surface receptors (SR) present on the plasma membrane of target cells. * The message is carried through cascade of protein-protein interactions. * Hormone is the first messenger. Then H-R complex sends signal across the membrane. * It elevates the concentration of intermediary molecules called second messengers. 3 * These messengers act as signal conducting molecules and bring out the effects Second messengers are:* cAMP Calcium phosphatidyl inositol (PI) diacyl glycerol (DAG). Hormones with cell surface receptors: I.A Hormones bind with cell surface receptors with cAMP as the second messenger such as MSH, PTH, CRH, ACTH, ADH, FSH HCG, LH, TSH Glucagon, Calcitonin Catecholamines and Retinoic acid. I. B Hormones having cell surface receptors; with cGMP as second messenger such as ANF (atrial natriuretic factor), NO (nitric oxide). I. C Hormones having cell surface receptors; second messenger is calcium or phosphatidyl inositol (PIP2) such as TRH, GnRH catecholamines, Acetylcholine, Gastrin and Oxytocin. I .D Hormones having cell surface receptors and mediated through tyrosine kinase such as Insulin and Somatomedin. I. E Hormones having cell surface receptors, but intracellular messenger is a kinase or utilize phosphatase cascade such as Erythropoietin, GH, PRL, TNF, Adiponectin, Leptin and Resistin. II. Hormones with intracellular receptors Mechanism of action of steroid hormones The group consists of sterol derived hormones which diffuse through cell membrane of target cells. • The receptors for them are present in nucleus and cytoplasm. • Such as Mineralocorticoids, Estrogens, Androgens, Calcitriol and Thyroxin 4 Signal Transduction The extracellular messenger, the hormone (H) combines with the specific receptor (R) on the plasma membrane; the H-R complex activates the regulatory component of the protein designated as G-protein or nucleotide regulatory protein. G proteins are so named, because they can bind GTP and GDP. When the hormone receptor complex is formed, the activated receptor stimulates the G protein, which carries the excitation signal to adenylate cyclase as figure below revealed. The hormone is not passed through the membrane; but only the signal is passed; hence this mechanism is called signal transduction. Cyclic AMP (cAMP) Adenyl cyclase converts ATP to cAMP (3',5'-cyclic AMP), and phosphodiesterase hydrolyses cAMP to 5' AMP.Cyclic AMP is a second messenger produced in the cell in response to activation of adenylate cyclase by active G protein. During hormonal stimulation, cyclic AMP level in the cell increases several times. 5 The level of cyclic AMP in the cell is regulated by its rate of production by adenylate cyclase (AC) and hydrolysis by phospho diesterase (PDE). The action of PDE is also regulated by hormones and drugs. Therefore, cellular level of cyclic AMP can be increased by inhibition of PDE. Calcium Based Signal Transduction Calcium is an important intracellular regulator of cell function like contraction of muscles, secretion of hormones and neurotransmitters, cell division and gene regulation. Rapid but transient increase in cytosolic calcium result from either opening of calcium channels in the plasma membrane or calcium channels in the Endoplasmic Reticulum (ER). The released calcium can be rapidly taken up by ER to terminate the response. The intracellular calcium concentration is low whereas extracellular calcium concentration is very high , maintaining a 10,000 fold calcium gradient across the membrane. The inside has a negative potential therefore influx of calcium is rapid. Even small increase in cytosolic free calcium can have maximal effect on calcium regulated cellular functions. There are mainly 3 types of calcium transport systems. a. Voltage gated calcium channels b. Sodium/calcium antiport transporter c. Calcium transporting ATPase. When cytosolic calcium increases, binding regulatory proteins, activation of several calcium binding regulatory proteins occurs. Calmodulin is expressed in various tissues and mediates the regulatory actions of calcium ions. Calcium binding causes conformational change in calmodulin resulting in 6 interaction with kinases, phosphatases. Intracellular calcium acts as amediator of hormone action either independently or in conjunction with cAMP. Hormones can increase the cytosolic calcium level by the following mechanisms : A. By altering the permeability of the membrane. B. The action of Ca-H+-ATPase pump which extrudes calcium in exchange for H+. C. By releasing the intracellular calcium stores. D. Calmodulin, the calcium dependent regulatory protein within the cell has four calcium binding sites. When calcium binds there is a conformational change to the calmodulin, which has a role in regulating various kinases. Hormones Acting through PIP2 Cascade The major player in this type of signal transduction is phospholipase C that hydrolyses phosphatidyl inositol in membrane lipids to 1,4,5-Inositol triphosphate (IP3) and Diacyl Glycerol (DAG) that act as second messengers. PIP3 (Phosphatidyl Inositol 3,4,5- phosphate) is another second messenger produced by the action of a phosphoinositide kinase. The phospholipase C may be activated either by G proteins or calcium ions. DAG can also be generated by the action of phospholipase D that produces phosphatidic acid which is hydrolyzed to DAG. The binding of hormones like serotonin to cell surface receptor triggers the activation of the enzyme phospholipase-C which hydrolyses the phosphatidyl inositol to diacylglycerol. IP3 can release Ca++ from intracellular stores, such as from endoplasmic reticulum and from sarcoplasmic reticulum. The elevated intracellular calcium then triggers processes like smooth muscle contraction, glycogen breakdown and exocytosis. PIP3 can be formed by the action of PI3-kinases that are activated through growth factors and cytokine mediated receptor tyrosine kinases. 7 Hormones with Intracellular Receptors i. The hormones in this group include the steroid hormones and thyroid hormones. They diffuse through the plasma membrane and bind to the receptors in the cytoplasm. ii. The hormone receptor (HR) complex is formed in the cytoplasm. The complex is then translocated to the nucleus. iii. In the nucleus, the HR binds to the hormone response elements (HRE) or steroid response elements (SRE) (Table 44.2). The SRE acts as an enhancer element and when stimulated by the hormone, would increase the transcriptional activity. The newly formed mRNA is translated to specific protein, which brings about the metabolic effects. Steroid hormones influence gene expression, so that the rate of transcription is increased. This would lead to induction of protein synthesis. Steroid receptors have been found to enhance initiation of transcription by formation of complexes at promoters. Insulin Signaling Pathway Insulin acts by binding to a plasma membrane receptor on the target cells. It has 2 alpha and 2 beta subunits. Insulin binds with the alpha units. This binding activates the tyrosine kinase activity of the beta subunit, leading to auto-phosphorylation of the beta subunit. This event, in turn, phosphorylates insulin receptor substrates (IRS). There are different IRS molecules, named as IRS 1 to 4. Activation of IRS2 results in activation of the PI-3 kinase, which eventually activates various protein kinases as figure below reveal. This leads to transcription of specific genes for key enzymes of glycolysis, such as glucokinase. There are more than 100 enzymes influenced by insulin. 8 9 10