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Lecture 35

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Biology (Sci)
BIOL 300
Siegfried Hekimi

th BIOL 300 November 30 2012 Lecture 35 Dr. Shock So far, we have discussed membrane bound cell- surface receptors • There is also a tiny class of intracellular receptors, whose ligands are able to freely diffuse into the cell The first pathway we will discuss is the nuclear hormone pathways; these are proteins are small and hydrophobic, and can cross the cell membrane • Some common protein include cortisol, estradiol, testosterone, etc. • Retinoic acid (vitamin A) is also hydrophobic and uses an intracellular receptor As soon as they bind to the receptor, they activate it; these active receptors are transcription factors which can activate gene expression Hydrophobic hormones have a very slow turnover time (very stable), so you can’t mediate in fast physiological responses • They mediate long responses, involving gene expression Two important words: • Agonist; any compound which acts like the hormone (bind and activates the receptor) • Antagonist; any compound which binds the compound and does not activate it (prevents action), and blocks access to the real hormone Pharmaceutical companies often screen for various agonists and antagonists in order to create drugs Nitric oxide, a gas, uses yet another intracellular receptor; it diffuses into the cell and binds guanylyl cycle • It’s most famous for causing male erection: • A signal from the brain (sexual arousal) • This is delivered to endothelial cells in blood vessels where NO is split off an arginine • NO is very unstable, but diffuses rapidly only a distance of about 1 cell diameter, i.e. to the surrounding smooth muscle cells • The NO will bind guanylyl cyclase, activating it which produces cGMP, which will cause SMC relaxation allowing blood flow to produce an erection 1 th BIOL 300 November 30 2012 Lecture 35 Dr. Shock • Viagra inhibits cGMP phosphodiesterase, which causes cGMP created by this pathway to last longer, allowing erections to happen more easily and for longer periods of time • This pill was found by chance; it was first tested to reduce chest pains, and was reported to produce stronger erections in male test subjects • They have tried to sell it to females; the entire pathway of arousal is the same (involving NO and increasing blood flow), but they wouldn’t buy it Signaling pathways can also be important in development; development can be divided into 3 categories: • Cleavage, or cell division, from giant egg into 1000s of smaller size, without increasing the overall volume • This is done to speed up development • Second, these 1000s of cells get patterned into head, tail, body, etc. regions,; this is known as pattern formation • This is done through transcription and signaling • Third, there are some morphogenesis reactions which actually caries out formation of these organs and appendages • This involves cytoskeletal remodeling We are mostly interested in the second phase You need signal memory; once you define a head region, it needs to be remembered for the entire life span • One mechanism is through autocrine signaling, which we have already seen, in which a small group of cells will signal to themselves to maintain their identities 2 th BIOL 300 November 30 2012 Lecture 35 Dr. Shock Another mechanisms occurs mainly at boundaries between segments in an embryo, involving positive feedback mechanisms between two cells • These two signaling systems may be from two adjacent cells which will end up belonging to two different tissue types Another common mechanisms involves positive feedback in which one transcription factor can actually cause transcription of itself, thus keeping its identity established over the whole life cycle of the cell An example of such a mechanism are Hox proteins, which determine the identity of our segments in our embryos • These are helped by regulators perpetuating the chromatin state (chromatin modifying factors) • Their expression are also helped by positive feedback loops Mutating Hox genes can lead to interesting mutations, like producing extra or missing wing pairs How are different tissues/cells fates specified? • Progressive subdivision of the embryo into smaller areas is achieved mainly by paracrine signaling • This is not useful to make a tissue interspersed with cells of a different fate (i.e. hair cells, which are located far away from each other within epidermal cells of the skin) We see that neuronal cells are very few, and evenly spaced between the much more frequent epidermal cells; this is not achieved through paracrine signaling The solution to this is a new signal transduction pathway known as Notch signaling; this is a pathway where both the ligand and the receptor are membrane bound 3 th BIOL 300
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