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PHSL233 lecture 04.doc

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University of Otago
Kirk Hamilton

PHSL233 Lecture 04 Signal transduction in Epithelia I When signalling molecules are sent out into the bloodstream, most cells will have contact with this signalling molecule. But only cells with the correct receptor can respond to this signal (ligand). So when ligand binds to receptor, this causes an activation of a effector which often is a enzyme. This enzyme will produce second messenger (Note ligand is the first messenger) which is a small chemical that goes off activing more effector which is a enzyme that can go through a serious of cascade pathways and eventually causing a cellular response. Different cellular response could be present for the same ligand depending on the cell. Ligands can be water or lipid soluble, water solubles such as peptide hormones cannot penetrate the plasma membrane so they bind to their receptor outside the membrane, usually an integral membrane protein. Lipid soluble such as steroid and thyroid hormones can diffuse through the plasma membrane so they bind their receptor in the cytoplasm of cell.Also a negative feedback is present some way along the pathway where it will act to decreae the signal and turn off the cellular response. Lipid soluble ligands aldosterone is a lipid soluble ligand that enters the plasma membrane and binding onto cytosol mineralocorticoid receptor. Once this ligand and receptor complex is formed, this complex then translocates into the nucleus and acts as a transcription factor with other components and activating transcription of mRNA.Aexample is SGK gene is activated, SGK is serine & glucocodicoid regulated kinase. SGK then will make more Na channels thus giving it a influx of Na ions. Different ligand receptor complex will bind to different regions of DNA thus expressing a different gene. Depending on what proteins are made, this will lead to different cellular response. RNApolmerase will help with transcription making a mRNAwhich then will go through translation making protein, could be signalling molecule or enzyme etc. Aldosterone Aldosterone are targetting the kidney collecting duct cells where signal transduction will occur. It is a steroid hormone of the ineralocorticoid family produced by the outer section of adrenal cortex called zona glomerulosa. In a response to low blood pressure, kidney releases angiotensinogen which goes through a serious of cacscade pathways in the blood and eventually turning into angiotensin II.Angiotensin II can cause blood vlessels to constrict and driving blood pressure up. Angiotensin II and low blood pressure can also directly activate the release of aldosterone from the adrenal cortex.Aldosterone travels in the blood via a carrier protein to the kidney.Aldosterone then binds to the mineralocorticoid receptor inside principal cells of the collecting duct of kidney and forms a transcription factor complex. This transcription factor complex then migrates into the nucleus where it will bind to promoter DNAupstream of specific gene. The group of genes that aldosterone promotes and binds to are called aldosterone-inducible genes on the DNA such as the SGK kinase gene. This gene then translates into aldosterone-induced proteins (AIPs) such as the SGK kinase protein.AIPs then act to increase the number of epithelial sodium channels at plasma membrane of collecting duct of kidney. This will increase Na re- absorption via increasing Na channel (ENaC) on apical membrane. This then also allow water to follow the Na. So Na and water re-enter the blood and increase in blood volume and blood pressure increases. This pathway takes about 1 hour to take effect and is a slow effect. There is a negative feedback control, as you re-absorb more sodium and water back in to the blood, this will cause a increase a blood pressure so “low blood pressure” stimuli is lost and aldosterone release ceases. Non-lipid ligands signalling molecules that are water soluble cannot pass the bilayer of the phosphate lipids, this means that their receptor must be found on the membrane. They can be grouped into G protein coupled receptors (GPRC), enzyme-linked receptors and ion channel linked receptors or ligand gated ion channels. GPCR So a ligand bind to a transmembrane receptor forming a receptor-ligand complex. conformational changes will then activate a closly related GTP protein which will dissociate from the receptor and binding to effector such as enzyme or ion channel (adenylyl cyclise). This then generate a second messenger (cAMP) which activates a second effector such as kinases (PKA), leading to cellular response. So to switch off this cellular response, receptor can become inactivated called desensitisation via phosphorylation. The receptor and the ligand can be taken up by cells called downregulation via endocytosis. We can inactivate the G protein and also negative feedback exists. G protein have a active state where it can go and act on the effector and also a inactive state. So during activation, where GDP is released and substituted for a GTP and G protein complex is now activated.After awhile GTP will hydrolysised, loosing a phosphate group and becoming GDP again and inactivating it. So associated with the GPCR, there will be a inactive G protein closely associated with it. The G protein is made up of 3 subunits of alpha, beta and gamma. There are many different types of G protien. In the absence of ligand the G protein is bound to receptor with alpha subunit binding to GDP. When ligand binds to receptor this will cause alpha subunit to bind to a GTP and dissociate from the beta and gamma subunits and it is now activated. Then activated alpha subunit then will bind and activates its effector (enzyme) while beta and gamma subunit may regulate ion channels directly. adenylyl cyclase, while another inhibitory G protien with alpha-i subunit which will inhibit the effector of adenylyl cyclase. Epinephrine (adrenaline) or anti-diuretic hormone (ADH) can activate the GPCR with alpha-s subunit. This will in turn activate the adenylyl cyclase effector which convertsATP into cAMP (cyclicAMP). cAMP is a secondary messenger and it acts on protein kinaseAand activating it. PKAis made up of 2 catalytic subunit and 2 regulatory subunit, on binding of cAMP, the catalytic subunits can be released and activated. Kinse can add phosphate group onto substrates thus activating it, so PKA activates a substrate by adding a additional phosphate group onto ser
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