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Lecture 8

Lecture 8 - small molecules.pdf

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University of Toronto St. George
Maurice Ringuette

Lecture 8 November 8, 2015:38 PM We can think of small molecules as signals can be sent through one cell to another cell. That barrier around the cell is a plams membrane. So how does the signal go into the cell? How does it pass across the membrane? Property of the signaling molecules decides the way it goes through the cell. We look through the classes of small molecules: we have charged molecules, polarized molecules. In the top we have hydrophobic molecules. Different classes of small signalling molecules. We know that the middle of the PM is hydrophobic, so looking at a charge we can tell that charge is not favorable to go through the PM. Hydrophobic molecules can pass through to the cytoplasm. BIO230 Page 1 NO: Extremely small molecule with two atoms. N and O. NO is made from deamination if AA residue arginine by the enzyme nitric oxide synthase. Once it is made its an example of a short range signalling molecule. It's a short range signalling molecule because its life time is short. It turns over very quickly and breaks down. Acts on smooth muscle and other targets. Example shown is smooth muscle: Epithelium There are 3 cell types involved in the signalling process. Smooth muscle cells cell surrounding a blood vessel. 1. Epithelial cells, most specifically endothelial cells because they are covering a blood vessel 2. Surrounding the blood vesseil is Muscle cell: can contract and control the flow of blood 3. Nerve - can send signals to the muscle and tell whether to contract or not. The way it works is indirect: we have three cell types. The end of the neuron can secrete acetylcholine which candiffuse through the tissue and bind to the end of the treceptor on endothelial cell. and activate the NO synthase. this is made within the cell from arginine. As soon as it is maade it can start to diffuse out of the cell. Nothing is stopping it from diffusing and leaving across the PM of the muscle cell. Within 10 seconds it is going to diffuse and rapidly diffuse inside to the muscle. Then it binds to a certain protein --> Binding leads to the conformational change in the protein--> changes the activity of the protein , this case it's an enzyme which drives the formation of gunanyl cyclase. GTP Converts it into cyclic GMP which relases the muscle to relax. NO signaling is embedded with a singal transcutuon pathway where multiple types of molecules are there. Acetylcholine, NO and then Lumen is where the blood is. Blood vessels have a special kind of blood vessels. This is specialized epithelium specials. cGMP. There is another cyclic moelcule cAMP later. Besides wpithlium cells there is a basal lamina. The neuro cells go cloe to the endothelial cells. It’s a very simple setup. Endothelial cells. We are looking at the acitvated nerve cell signalling to an endothelial cell. (image 1) . Activated nerve Medical aspects: Nitroglycerine can be used to treat heartpain. It is converted to NO by body, this relaxes blood vessels so it reduces the cell is releasing acetylcholine, whole bunch of proteins are activated. NO is activated. It activates arginine. Oyu want the work load on the heart. You can take advantage of the singalling blood vessels to relax, less work load on the heart pathway to treat heart pain. Small hydrophobic moelcules that pass through the membrane. There are multiple characterists. - Steroid hormones. Structure of cholesterol is four rings in a row. Estradiol and testosterone. All made from cholesterol. All these are classes of steroid. - Thyrid hormones: made from tyrosine. Includes metabloic rate. - Retinoic acid: - Vitamin D. - affects metabolism These all are small hydrophobic molecules and diffuses into the blood stream.and affects cells at a distance. When they enter the PM passively. they bind to this molecule inside . They are called as nuclear receptor super family mebers > they are hydrophobic. They have carrier proteins which will get them through the blood stream. Little bit if them are continuously released from the carrier protein and they can pass through the PM interact with the receptors. The receptores have a common organization to them. They have a binding site for small hydrophobic molecules and dna. So they bind to dna and change gene transcription. Signalling is changing the gene trasncription BIO230 Page 2 Based on those two characterists : binding site to hydrophobic molecule and DNA, you can go through a sequnce from the genome and identify that there are 48 of these in the genome. You can identify the receptor, but only about half of these are the ligands known. So for those that the ligands are not known is called as orphan nuclear receptors. And so we suspect that they must be doimng something important because they have a binding site for dna and small moleucles. We don’t know what the signalling is for. The thing is we can do dna sequcening and find the domains. But its hard to isolate small hydrophobic moelcule do binding assay for purified receptors, do gentics to dna moelcuesl and test the effect. So we are mising lots of thes epairs. Orphan nuclear receptors To the pairs that we do know, there is an impact to the small molecule binding on receptors basic principle, when we have binding there is an conformational change in the protein which affects the binding properties or the enzymatic activity. Thereceptors are not enzymatic enzymes so it change is affecting the conformations property. The long one is the inactivating domain it has is multiple folded domains in the polypeptide chain. Dna binding domain, ligand binding domain so on. Normally this is bound by a inhibited proteind molecule so it wont interact with dna. But when the ligand is present it will bind and the inhibitory protein is expelled so dna binding site is poen and the conformational change is optimal for dna binding. Confomrational change effects wither the binding property or the enzymatic proeprty. k BIO230 Page 3 This is the crystal strucutre where the alpha helices with indivudal receptors when the ligannd binds to the receptor there is a major change in conformation. These receptors are TF and in any transcrition response there is going to be a primary effect on transcription and some of the genes that were transcribed will encode the TF itself. So you change the expression of TF and it can additionally change the transcription in a second wave of regulation. We have seen this before in segmental pattern in early drosophila embryo in a cascade of signal transduction We have a primary effect on gene transcription and they have an effect on other genes. Turning some on and off. BIO230 Page 4 Those were examples of how signaling molecules can pass through the lipid bilayer all by themselves. . Now lets look at where n small moelcules need help snd cannor pass.cannot pass on its ow We look at channels… They open up the space and passes through the membrane. And its water filled, and moelcules pass through it This is where we are looking at the class of charged molecules. Ion channels can function in a whole array of different activties. the electrical excitability of muscle cells. Outside of that there is a leaf closure response in plants, single celled paramecium can reverse their reaction retract after bumping into something. These hannels are present in all animal cell.s best known in nervous system but present in many cells BIO230 Page 5 Ion channels can function in a whole array of different activities. Cartoon of ion channels themselves. Have narrow selective pores. Selctive for specif ions. Can open close rapidly. Many ions can pass through them in little time. The key point here is that the transport is passive. The channel when its open, It's not grabbing a molecule and forcing it through. It just opens the gate, and the moelcules wants to go through because of a gradient. The massive flow is because of the graident that is built up. Moelcules will flow from high [] to low []. these BIO230 Page 6 These ion channels are regulated. They are controlled by the cell. Can be regulated in multiple ways. • Voltage gated channel:channel is closed or open based on electrical charges on opposite sides if the membranes. Based on +/- charge • Binding of a ligand: you can have a small molecule or a protein bind to the outside/ inside of the channel to open them up. Idea is there is an molecular interaction and conformational change and an opening of a channel pore. The conformational change is the opneing oif the pore. • Mechanically gated channel: physical force that opens the channel up. - Previously Sterocillia: that is on top of the sound waves it will move past each other, when sound waves moves the tether will open mechaincally gated channels. Those are how channels can be opoend and closed. So other half of the equation is how the gradients of ions. The cahrt shows the gradietns comparing the Shows how the gradients goes from [] inside the cell to the [] outside the cell. Na+ is higher outside. And its prone to go in. K is high inside and prone to go out. So the channels are open and the ions will flow down the []gradient. The asterisk: the cell does contain equal quantities of + / - molecules. The cell is neutral. No net positive / - charge. Chloride donest add up, the number of + charged moelcues donet ad up. All of the macromoelcuesl are also charges , dna, etc and they will equally contribute to the gradinet. Lets focus o Na and K gradients. BIO230 Page 7 It sets up the potential for an action potential. We can have vboltage gated na channels responding to action potential The first step invovles leakage of K ions outside of the cell. Left: we can see where there is no leakage of K+ ions. We have an equal mix of + and - charges. In both sides. Exact balance of charges. No membrane potential. In excitable cells: there is a slight leak of K going out of the membrane the channels allow a slight leak of K. the leak can occur but its restricted because of the difficulty in separating charges. You start to pull the cahrges to that side, from inside and that will leave the + ions close to the membrane. +/- don’t want to be far apart. They are pulled down bvy the [] gradient but they are pulled back from the electrical gradient. This is the ground state for the exiftable cells. The prioteins along the membrane will be in a specific confomration. What happens What happens for a sginal to occur is there is much more Na outside than oinside. So Na will go nto the cell, and distrupt the region of + charge. So the charge is altered and protein will chnge its conformation. This is how signals are sent. The change can sent a travelling wave of depolarization. BIO230 Page 8 The first step is to open one of the Na + channels. When you open them there is a rush of + ions in.
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