Zaid Emad. Ahmad Gharaibeh. Ebaa Alzyadneh

Transcription

1 28 Zaid Emad Ahmad Gharaibeh Ebaa Alzyadneh

2 First of all, I am so happy to have this chance to write the last sheet of this great subject, I wish I can present it in a simple way that can help you while studying (cutting). Please complete reading this sheet as there is a message I want you to read at the end. Ladies and gentlemen,,, here we go,,, Introduction : In the previous 4 lectures, we have learnt some of the basic concepts about signal transduction mechanisms. We learned that there are 2 basic types of receptors : 1) Membrane receptors, which is divided into 3 subtypes : A) Ligand gated Ion channel receptors. B) G-protein coupled receptors. C) Enzymes linked receptors. 2) Non-membrane receptors: for example, A) Nitric oxide receptors. B) Steroid hormone receptors. (Which I will present in this sheet) We talked also about some types of second messengers such as: CAMP, CGMP, IP3, DAG, Calcium..Etc. Neurotransmitters and the types of receptors: The receptors for neurotransmitters are divided into two types: 1) Ionotropic receptors 2) Metabotropic receptors 3) Tyrosine Kinase receptors First of all, ionotropic receptors are characterized by the presence of an ion channel within the receptor itself, so when the NT binds to the receptor the channel opens and the ion flow causes a change in the membrane potential. In this type of receptors, there is NO second messenger, therefore the response is FAST. 1 P a g e

3 On the other hand, metabotropic receptors are G-protein coupled receptors ( there is no channel ) and when the receptor is activated by the NT the Alpha subunit dissociates and either opens a channel away from the receptor or induces cellular signaling by binding to an enzyme or changes gene expression. Here the response will need a second messenger, therefore the response is SLOW. Metabotropic effect lasts longer. Note that some NT might bind to Tyrosine kinase receptors. Modulating of the NTs activity happens by two ways: (how to regulate the NTs) 1) Enzymatic degradation: for example there are drugs for increasing the activity of the Ach by preventing the work of Acetylcholinesterase. 2) Uptake by the presynaptic cell or by glial cells. So we can prolong the action of the NT if we prevent the up taking or, inhibit the enzyme responsible for degradation. Let us start with the new material, Signaling of steroids and thyroid hormones: - These hormones plasma are bound to proteins in the blood plasma to increase their half-life and decrease their clearance. - When these hormones crosses the plasma membrane they need to dissociate from their bounding proteins. 1) Steroids ( testosterone, cortisol, estrogen, progesterone,,, ) These hormones are lipophilic so they don t need cell surface receptors to enter the cell, they can diffuse easily throw the plasma membrane. 2 P a g e

4 While moving throw the blood these hormones are bounded to carrier proteins which may be specific or not specific. When they reach the target cell they diffuse throw the membrane without the carrier protein to find their receptors either in the cytosol or in the nuclear envelope. When they bind to the cytosolic receptor (the receptor has 2 binding sites: hormone binding domain-binding site- and DNA binding domain) they will form a complex (hormonereceptor complex) which will enter the nucleus and dimerize with another identical receptor and this dimer will bind to a specific region on the DNA called hormone responsive element (HRE) which proceeds the gene that will be expressed. The dimer will induce gene translation. (Refer to the figure at the end of the page to imagine the concept) 2) Thyroid hormones ( T4 and T3 ) : The 2 types of the thyroid hormones are T3 which is active, and T4 which is inactive and must be converted to T3 to enter the cell. In the blood these hormones are bounded to a carrier protein called thyroid binding globulin (TBG). When they reach the target cell they diffuse throw the plasma membrane (if the hormone is T4 it must be converted to T3) to find the receptors in the nuclear 3 P a g e

5 envelope (no receptor in the cytosol) and form a hormone-receptor complex which dimerize with another different complex composed of a Vitamin A derivative called 9- cis-retinoic acid bounded to a RXR receptor. Then they bind to the HRE on DNA to stimulate gene expression. -Thyroid is important in CNS development and growth during infancy. -After puberty thyroid mainly affects metabolism. Note that the state of the hormone is dynamic between being bound to a protein and being free, it depends on the concentration of the free hormones. So if we increase the concentration of the hormone we will get an action. However, when the free hormones are presented in the blood it might be cleared. Here we must define the clearance rate which means how much of the hormone is cleared from the plasma per minute. If the clearance rate increases, the binding of the hormone will decrease, and if the half-life of the hormone increases, the binding will increase. Factors that determine the cellular response of hormone: the amount of free hormones, the amount of hormone receptors, secretion of hormones, degradation of the hormone (metabolism). 4 P a g e

6 The higher the protein binding percentage is>>the higher the plasma half life>>the lower the clearance. 5 P a g e

7 Types of transport proteins to which the hormones are bounded in the blood: (Specific and Nonspecific) Hormone binding can be specific for certain proteins that are specific for certain hormones ex: thyroxin has a certain binding protein called thyroxin globulin. -sometimes binding can be nonspecific (ex: albumin) An overview about how the Hypothalamus can induce the release of LH and FSH: First, the hypothalamus release a hormone called Gonadotropin-releasing hormone (GnRH) which binds to the receptor on the surface of the anterior pituitary gland cells, these receptors are Gq-protein coupled receptors, the alpha subunit will bind to phospholipase C which will convert the phospholipid into IP3 and DAG. IP3 will induce the release of Ca from the smooth ER, then Ca ions in turn will induce exocytosis of the 6 P a g e

8 vesicles containing LH and FSH. ANP, NO receptors and TGF BETA receptors: When ANP (Atrial natriuretic peptide) or NO (Nitric Oxide) binds to its receptor which is an enzyme linked receptor, it will induce Guanylyl cyclase to convert GTP into C-GMP, which will bind to protein kinase G and this will cause relaxation of smooth muscles (vasodilation). TGF BETA is the signaling mediator for fibrosis during healing process after having an injury in the skin for example. On the other hand, TGF BETA can cause fibrosis of the kidney and thus preventing it from performing its function. The receptor for TGF BETA is called Serine/Threonine kinase. Third messenger: -Sometimes used but not as important as second messenger -Any signaling molecule going from outside to inside of nucleus or inside to outside is called third messenger. 7 P a g e

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10 Finally, here comes the message that I want to deliver: في البداية هللا يعطيكم العافية إن شاء هللا تكون نهاية فصل سعيدة عليكم جميعا و إن شاء هللا يكون هذا الفصل خطوة لألمام في عالم الطب العظيم اذا وصلت لهذا الشيت اعرف انك قطاعة النه الي عمله corrnciion نفسه لسا ما وصله. و لكل واحد ما حصل ع الي بتمناه هاي لسه البداية تذكر دائما انه طريق الطب طويل بس في اآلخر لما توصل ل هدفك و تطلع وراك و تالقي العقبات و الصعاب الي مريت فيها راح تحس بالفخر و راح تحس فيه أكثر لما تشوف حالك انقذت حياة إنسان و زرعت االبتسامة ع وجهه. و لكل واحد حس انه قرب يستسلم اتذكر فرحة أهلك لما تخرجت من التوجيهي و دخلت كلية الطب و رفعت راسهم. في النهاية شكرا الكم جميعا و اسف على التأخير موفقين بإذن هللا دفعتي العظيمة أحبكم أخوكم و زميلكم زيد عماد Good Luck to you all Hope you MAX the final Yours faithfully, Ahmad Gharaibeh 9 P a g e