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Intracellular Receptors ****Structure: consists of 3 parts:1. Steroid-binding domain:- Steroid hormone and Thyroid hormone binding sites- Associated with heat shock proteins which mask the DNA-binding domain of a resting receptor2. DNA-binding domain:- Contains 2 loops of zinc fingers- Zinc fingers associate with the Hormone-Responsive Elements(HREs) in the target genes- HREs are palindromic sequences in the target genes unique to each hormone3. Transactivation domain:- Involved in activating transcription of the target genesCytoplasmic Receptors1. Non polar steroid hormone diffuses through the plasma membrane of the target cells and binds to the ligand-binding domain of the cytoplasmic receptor2. 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 nucleus4. 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 inhibited5. Stimulatedthe proteins synthesized mediate reactions which are attributed to the biological actions of the steroid hormoneInhibited 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 hormoneNuclear Receptors1. 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 receptors2. Hormone-receptor complex undergoes a conformational change and heat-shock proteins dissociate3. With the 2 zinc fingers in the DNA-binding domain, the Hormone-receptor complex binds to ½ of the palindromic sequence of the HRE; the other ½ of the HRE is ALWAYS occupied by retinoic acid receptor (RXR) 4. 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 cellswhich are attributed to the biological actions of steroid hormone or thyroid hormone5. If a co-repressor binds to the complex, transcription of the target genes is repressed (inhibited) and certain proteins are not synthesizedThe 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 acidsADH- 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 ½ life of neurophysin > ½ of ADH- Main function- puts aquaporins in collecting duct of kidney, water will diffuse out through the aquaporinsStimuli for the release of ADH from the post pit.o Dehydration from excessive sweating (hyperhydrosis), or from lack of water intakeo Hemorrhaging blood loss, leads to hypovolemia, which can also be caused byexcessive vomiting (hyperemersis), when vomiting occurs, fluid loss from the GItrack 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 fluid shift o Hypotension- decrease in blood pressure stimulates ADH, can result from generalized vasodialation, can also result from hypovolemiao Hypovolemia- Decreased BV decreased VR Decreased EDV decreased SV decreased CO decreased BPo 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 dehydrationMajor 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 atthe 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 tocause vasoconstriction  increases the TPR  increases blood pressure (its vasopressiveor 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.ADH Dysfunction – HYPOFUNCTION - ADH hypofunction is called Diabetes Insipidus (DI)- 2 types :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 the collecting ducts - Drugs such as lithium decrease V2 receptor density (down regulation) and aquaporin translocation- Chronic renal disease/infections (such as pyelonephritis) interfere with the osmotic gradient in the medullary interstitium surrounding the collecting ductsGDI- gestagenic- During pregnancy, horms released form placenta (human placental lactogen)- Activate enzyme = basopressinase- breaks down ADH in the blood stream


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UMD BSCI 447 - Intracellular Receptors

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