Endocrinology Introduction PDF

Endocrinology introduction 395-406 sergeenko The endocrine system The endocrine system, in concert with the nervous system, is responsible for homeostasis. Growth, development, reproduction, blood pressure, concentrations of ions and other substances in blood, and even behavior ar...

Endocrinology introduction 395-406 sergeenko The endocrine system The endocrine system, in concert with the nervous system, is responsible for homeostasis. Growth, development, reproduction, blood pressure, concentrations of ions and other substances in blood, and even behavior are all regulated by the endocrine system. Endocrine physiology involves the secretion of hormones and their subsequent actions on target tissues The classic endocrine glands are the hypothalamus, anterior and posterior lobes of the pituitary, thyroid, parathyroid, adrenal cortex, adrenal medulla, gonads, placenta, and pancreas. The kidney also is considered to be an endocrine gland, and endocrine cells are found throughout the gastrointestinal tract. HORMONE SYNTHESIS Three General Classes of Hormones Proteins and polypeptides Steroids Derivatives of the amino acid tyrosine Proteins and Polypeptides insulin,glucagon,parathyroid hormone,GH,TRH,prolactin Synthesized on the rough ER First made as a preprohormone which is cleaved into a prohormone Stored in vesicles as an active hormone and are released by exocytosis Trigger for release can be cAMP, calcium, or some other chemical  Proteins and Polypeptides Figure 9.2 steps in synthesis 1. In the nucleus, the gene for the hormone is transcribed into an mRNA. 2. The mRNA is transferred to the cytoplasm and translated on the ribosomes to the first protein product, a preprohormone. the signal peptide attaches to receptors on the endoplasmic reticulum via “docking proteins.” Translation then continues on the endoplasmic Reticulum 3. The signal peptide is removed in the endoplasmic reticulum, converting the preprohormone to a prohormone 4. The prohormone is transferred to the Golgi apparatus, where it is packaged in secretory vesicles 5. The final hormone is stored in secretory vesicles until the endocrine cell is stimulated. For example p398  Steroid Hormones. cortisol,aldosterone,estrogen,progesterone,testostetone 1.25 dihydroxycholecalcoferol Derived from cholesterol Very little storage Because they are lipid soluble, they diffuse across the cell membrane into the interstitial fluid and then the blood Amine Hormones thyroxine,epinephrine,norepinephrine Derived from tyrosine Includes thyroid and adrenal medullary hormones Thyroid is stored in the thyroglobulin Adrenal medullary hormones include epinephrine and norepinephrine Hormone Secretion, Transport, and Clearance Each hormone has its own characteristic onset and duration of action; epinephrine and norepinephrine are secreted within seconds and develop full action within another few seconds; thyroxine may require months for full efffect Feedback Control Negative feedback prevents overactivity of hormone systems Surges of hormones can occur with positive feedback (i.e. LH) Cyclical variations occur in hormone release (seasonal changes, aging, diurnal cycles, and sleep)  negative feedback negative feedback was discussed in the regulation of arterial BP. A decrease in arterial blood pressure is detected by baroreceptors. In endocrine systems, negative feedback means that some feature of hormone action, directly or indirectly, inhibits further secretion of the hormone. Negative feedback loops are illustrated in Figure 9.3 hypothalamus the hypothalamus secretes a releasing hormone, which stimulates secretion of an anterior pituitary hormone which in the testis) to cause secretion of the hormone (e.g., testosterone), which acts on target tissue. Anterior pituitary and the hypothalamus to inhibit their hormonal secretions. Long-loop feedback means that the hormone feeds back all the way to the hypothalamic pituitary axis. Short-loop feedback means that the anterior pituitary hormone feeds back on the hypothalamus Positive feedback is rare. is explosive and self-reinforcing. A hormone has biologic actions that, directly or indirectly, cause more secretion of the hormone. For example, the surge of luteinizing hormone (LH) that occurs just before ovulation is a result of positive feedback of estrogen on the anterior pituitary. LH then acts on the ovaries and causes more secretion of estrogen Regulation of receptors The responsiveness of a target tissue to a hormone is expressed in the dose-response relationship in which the magnitude of response is correlated with hormone concentration. Hormones determine the sensitivity of the target tissue by regulating the number or sensitivity of receptors. 1. Down-regulation of receptors A hormone decreases the number or affinity of receptors for itself or for another hormone. For example, in the uterus, progesterone down-regulates its own receptor and the receptor for estrogen. 2. Up-regulation of receptors A hormone increases the number or affinity of receptors for itself or for another hormone. For example, in the ovary, estrogen up-regulates its own receptor and the receptor for LH MECHANISMS OF HORMONE ACTIOn AND SECOND MESSENGERS Hormone actions on target cells begin when the hormone binds to a membrane receptor, forming a hormone-receptor complex. In many hormonal systems, the hormone-receptor complex is coupled to effector proteins by guanosine triphosphate (GTP)–binding proteins (G proteins). The effector proteins usually are enzymes, either adenylyl cyclase or phospholipase C. When the effector proteins are activated, a second messenger, either cyclic adenosine monophosphate (cAMP) or inositol 1,4,5-triphosphate (IP3), is produced, which amplifies the original hormonal signal and orchestrates the physiologic actions Fig. 9.4 Steps involved in the adenylyl cyclase (cAMP) mechanism of action. See Cell Membrane Phospholipid Second Messenger Activate phospholipase C attached to the membrane IT causes phospholipids in the cell membrane to split into the second messengers diacylglycerol [DAG]and inositol triphosphate IP3 IP3 mobilizes Ca from internal stores, such as the endoplasmic reticulum, the Ca in turn activates protein kinase C which activates and deactivates enzymes mediating the hormone responses. DAG futher enhances the activity of protein kinase C Hormones that use this system include: angiotensin II, catecholamines, GnRH, GHRH, oxytocin, TRH, and vasopressin Calcium-Calmodulin Second Messenger A.Calcium entry is initiated by (1) changes in the membrane potential that opens calcium channels,or (2) hormones that interact with membrane receptors and open the calcium channels B. Calcium binds with calmodulin(has 4 binding sites) C.When 3 binding sites are filled, the calmodulin initiates multiple effects inside the cell Catalytic Receptor Mechanisms Some hormones bind to cell surface receptors that have, or are associated with, enzymatic activity on the intracellular side of the cell membrane. These so-called catalytic receptors include guanylyl cyclase, serine/ threonine kinases, tyrosine kinases, and tyrosine kinase–associated receptors. Guanylyl cyclase catalyzes the generation of cGMP from GTP. ANP causes activation of guanylyl cyclase and conversion of GTP to cGMP. cGMP then activates cGMP-dependent kinase, which phosphorylates the proteins responsible for ANP’s physiologic actions. Guanylyl Cyclase Hormones acting through the guanylyl cyclase mechanism are also listed in Table 9.3. Atrial natriuretic peptide (ANP) and Nitric oxide (NO) act through a receptor guanylyl cyclase.. Serine/Threonine Kinases As previously discussed, numerous hormones utilize G protein– linked receptors as part of the adenylyl cyclase and phospholipase C mechanisms (see Table 9.3 In addition, Ca2+- calmodulin-dependent protein kinase (CaMK) and mitogen-activated protein kinases (MAPKs) phosphorylate serine and threonine in the cascade of events leading to their biologic actions.  Tyrosine Kinases Tyrosine kinases phosphorylate tyrosine moieties on proteins and fall in two major categories.. Receptor tyrosine kinases have intrinsic tyrosine kinase activity within the receptor molecule, ♦ Receptor tyrosine kinases have an extracellular binding domain that binds the hormone or ligand When activated by hormone or ligand, the intrinsic tyrosine kinase phosphorylates itself and other proteins. 1.One type of receptor tyrosine kinase is a monomer (e.g., nerve growth factor [NGF] and epidermal growth factor receptors, see Fig. 9.6A). 2.Another type of receptor tyrosine kinase is already a dimer (e.g., insulin and insulin-like growth factor [IGF] receptors, see Fig. 9.6B 3.♦ Tyrosine kinase–associated receptors (e.g., growth hormone receptors, see Fig. 9.6C)  3.Enzyme Linked Hormone Receptors Fig. 9.6C) Hormone binding site is on the outside of the membrane and their catalytic or enzymatic binding site is on the inside of the membrane. An enzyme-linked receptor—the leptin receptor. The receptor exists as a homodimer (two identical parts), and leptin binds to the extracellular part of the receptor, causing phosphorylation (P) and activation of the intracellular associated janus kinase 2 (JAK2). This mechanism causes phosphorylation of signal transducer and activator of transcription (STAT) proteins, which then activates the transcription of target genes and the synthesis of proteins. JAK2 phosphorylation also activates several other enzyme systems that mediate some of the more rapid effects of leptin. Y, specific tyrosine phosphorylation sites.  Steroid and Thyroid Hormone Mechanism steroid hormones act slowly (taking hours). The steps in the steroid hormone mechanism (shown in Fig. 9.8) are described as follows: 1. The steroid hormone diffuses across the cell membrane and enters its target cell (Step 1), where it binds to a specific receptor protein (Step 2) The steroid hormone binds in the E domain located near the C terminus. The central C domain is highly conserved among different steroid hormone receptors, has two zinc fingers, and is responsible for DNA binding. With hormone bound, the receptor undergoes a conformational change and the activated hormone-receptor complex enters the nucleus of the target cell. 2. The hormone-receptor complex dimerizes and binds (at its C domain) via the zinc fingers to specific DNA sequences, called steroid-responsive elements (SREs) located in the 5′ region of target genes (Step 3). 3. The hormone-receptor complex has now become a transcription factor that regulates the rate of transcription of that gene (Step 4). New messenger RNA (mRNA) is transcribed (Step 5), leaves the nucleus (Step 6), and is translated to new proteins (Step 7) that have specific physiologic actions (Step 8).