Intracellular Receptors Structure consists of 3 parts 1 Steroid binding domain Associated with heat shock proteins which mask the DNA binding domain of a resting Steroid hormone and Thyroid hormone binding sites receptor Zinc fingers associate with the Hormone Responsive Elements HREs in the target genes 2 DNA binding domain Contains 2 loops of zinc fingers HREs are palindromic sequences in the target genes unique to each hormone 3 Transactivation domain Involved in activating transcription of the target genes Cytoplasmic Receptors 1 Non polar steroid hormone diffuses through the plasma membrane of the target cells and binds to the ligand binding domain of the cytoplasmic receptor 2 The steroid hormone receptor complex undergoes a conformational change that results in the dissociation of the heat shock proteins 3 The steroid hormone receptor complex undergoes compaction and translocates into the nucleus 4 The steroid hormone receptor complexes dimerize and binds with 4 zinc fingers to the HRE Hormone Responsive Element on the target genes to regulate transcription transcription may be stimulated or inhibited 5 Stimulated the proteins synthesized mediate reactions which are attributed to the biological actions of the steroid hormone Inhibited the absence of these proteins in the target cell results in the inhibition of certain reactions which are attributed to the biological actions of the steroid hormone 1 Steroid hormone or thyroid hormone diffuses through the plasma membrane and then through the nuclear membrane to bind to the ligand binding domain of its receptors 2 Hormone receptor complex undergoes a conformational change and heat shock proteins Nuclear Receptors dissociate 4 3 With the 2 zinc fingers in the DNA binding domain the Hormone receptor complex binds to of the palindromic sequence of the HRE the other of the HRE is ALWAYS occupied by retinoic acid receptor RXR If transcription is to be stimulated in the target gene a co activator binds to the bound hormone receptor complex the proteins synthesized mediate reactions in the target cells which are attributed to the biological actions of steroid hormone or thyroid hormone If a co repressor binds to the complex transcription of the target genes is repressed inhibited and certain proteins are not synthesized 5 The 2 Posterior Pituitary Hormones ADH and Oxytocin Antidiuretic hormone ADH and Oxytocin are synthesized by the hypothalamus Transported via the hypothalamic hypophyseal tract to the posterior pituitary ADH and Oxytocin are stored released from the posterior pituitary Cosecreted with neurophysin Both ADH and Oxytocin are nonapeptide each composed of 9 amino acids ADH Antidiuretic Hormone aka AVP Arginine Vasopressin ADH AVP is synthesized by the hypothalamus released via the hyposeleal tract to the posterior pit ADH is concentrated and bound by a protein called Neurophysin in eqimolar concentration The amount of ADH the about of neurophysin bound hence the neurophysin conc in the blood stream is used to estimate the concentration of ADH released The life of neurophysin of ADH Main function puts aquaporins in collecting duct of kidney water will diffuse out through the aquaporins Stimuli for the release of ADH from the post pit o Dehydration from excessive sweating hyperhydrosis or from lack of water o Hemorrhaging blood loss leads to hypovolemia which can also be caused by excessive vomiting hyperemersis when vomiting occurs fluid loss from the GI track stimulates fluid shift from the blood stream to replace fluid loss decrease in blood volume o Hyperosmolality of blood Increased blood osmolality can be caused also by intake fluid shift o Hypotension decrease in blood pressure stimulates ADH can result from generalized vasodialation can also result from hypovolemia o Hypovolemia Decreased BV decreased VR Decreased EDV decreased SV decreased CO decreased BP o Estrogens this explains the water retention bloating associated with the menstrual cycle can also happen with progesterone ALCOHOL INHIBITS ADH RELEASE cause more urine output dehydration Major Biological Actions of ADH Has 2 types of receptors based on location v2 and v1 ADH binds to cell surface receptors called V1 and V2 receptors ADH binds to V2 receptors to induce the cAMP signal transduction mechanism ADH binds V1 receptors to induce the PIP IP3 signal transduction mechanism 1 ADH binds to V2 receptors on collecting ducts in the kidneys to stimulate water reabsorption the collecting ducts are impermeable in the absence of ADH increasing the blood volume and decreasing urine volume its antidiuretic effect a ADH stimulate the translocation of aqueous cannels called aquaporins to insert at the plasma membrane of the cells in the collecting duct to allow water reabsorption FACULTATIVE WATER REABSORPTION 2 ADH binds to V1 receptors on the smooth muscle cells in the wall of the blood vessels to cause vasoconstriction increases the TPR increases blood pressure its vasopressive or vasoconstrictive effect 3 ADH binds to V1 receptors on hepatocytes to stimulate the production of clotting factors VIII and von Willebrand factor from vascular endothelial cells hence ADH analogs such a desmopressin are used pharmacologically in the management of some bleeding disorders HYPOFUNCTION ADH Dysfunction 2 types ADH hypofunction is called Diabetes Insipidus DI 1 Neurogenic DI also known as Central DI destruction of structures in the CNS Causes Head trauma damage to the hypothalamic nuclei synthesizing ADH Autoimmune autoantibodies directed against ADH secreting hypothalamic neurons Destruction of the infundibulum contains the hypothalamic hypophyseal tract Hypophysectomy partial complete removal of the pituitary 2 Nephrogenic DI renal insensitivity to ADH Causes Congenital defect of V2 receptors dysfunctional V2 receptors on the cells of Drugs such as lithium decrease V2 receptor density down regulation and the collecting ducts aquaporin translocation Chronic renal disease infections such as pyelonephritis interfere with the osmotic gradient in the medullary interstitium surrounding the collecting ducts During pregnancy horms released form placenta human placental lactogen Activate enzyme basopressinase breaks down ADH in the blood stream whieh Hypofunction due to receptor disfunction higher than normal levels of the hormone in GDI gestagenic decreases ADH levels the blood stream Features of DI Passage of copious amounts of very dilute urine high urine volume low urine