The tip link, actually people later found actually some special molecules actually in for the tip link. There are two here. These molecules, you can use the antibody for CDH23. You can see this is antibody staining. For another one, you have also the PCTDH15 antibody. And so if you knock out these proteins, the structure of tip link are destroyed and then you have hearing loss. You cannot hear anything. And also, for the experiments it's actually quite simple. In the early days people just actually switch this so when isolate the hair cell, put it in the solution, do the recording, you can get the mechanical response. But if you put the cell in a solution, that solution is the low calcium without calcium inside. And then this tip link will break. And then you give another mechanical stimulation. You cannot get any response. So that's actually link the proposal actually to the reality. So it seems the tip link can really, even the drop, we're pulling the gate open. So also it's quite interesting, the hair cell sit, this region, the tip region actually is in a link solution, [FOREIGN]. Now the link solution actually quite different than the ionic composition. It is different from they have quite high potassium ions. Just like a solution. This is quite strange. So if we have high potassium solution for whole cell like a neuron, what ever happened to the neuron? Okay, we isolate the neuron and then you diffuse with high potassium solution, what will happen? [FOREIGN]. Well it'll cause depolarization, why? >> [INAUDIBLE] >> Depolarization? Reverse potential? >> Yeah, reverse potential where [INAUDIBLE] >> Okay, so we know actually for most there, actually, including neurons, the intracellular solution is a high potassium. Low sodium, but the isolyte solution and the extracellular solution there is low potassium, high sodium ion. So if you increase the extracellular potassium and then the cell will depolarize. So for this region, because actually, it's special, actually, just covered by the high potassium solution. When you have these solutions there, you think about, this cell is already depolarized at its resting state, right? But actually either way not, why? >> [INAUDIBLE]. >> Okay, potassium changes. No, or another way to say it maybe is obviously no potassium channel, right? So either you have some potassium channels there. But the potassium channels always close. And another situation would be there isn't any potassium channel. And then of course you increase the potassium then you will not affect the potential. Indeed for this region there is no other channel except for this channel. So this high potassium actually will not affect the resting membrane potential of this cell. It's okay for then. And then, when you have a mechanical force to open this channel, then the potassium ion will go into the cell. Then the polarization of the cell, okay? Causes depolarization. Depolarization will activate those voltage, created a calcium channel. The calcium channel open and then the calcium will go in and the neurotransmitter, they will be released. This is the cell respond to the mechanical stimulation. So, we also know actually the cell can be, if you give another stimulation in another direction, maybe the cell will have been polarized. That's actually the recording demonstrate already. So can you think of a way to achieve this for a cell? So if at a resting state already some of those channels open, and then you push another way, the tip link then will more relax and channels are closed. And of course, then you have polarization, right? Indeed, this is what happened to the cell. At the resting state there was already some of the channel open. Keep a basal depolarization. So if you move to another way the channel will be closed. So these cell respond to the mechanical force by such a direct way that is without any biochemical steps, intermediated biochemical steps you can work with, right? It's really just a direct gating, a spring, pulls the gate open. So, for this, of course, the speed is good. It's a very fast response. But what's the problem? No amplification, right? We talk about, actually in the photo receptor because it's a biochemical reaction. One single molecule activated. The signal will be amplified about 20,000 fold. LIke, why are you adopted where active with about 20 GMP molecules. And 1 PDE will hydrolyze about 1,000 cyclic GMP molecules, right? But here, then you don't have the amplification, there's a problem, for this system Because we need really sensitive auditory detection. How can you achieve the amplification here, okay? Neurotransmitter release, how you amplify the signals? If 1 kelvin comes in, the mass increase might be just, for example, the release is just one reciprocal and then you want to amplify this signal. Simultaneously you can release multiple vesicles. That's actually amplification, right? Then the signal propagate to the downstream is quite strong. Indeed, actually in the hair cell, there are some kind of, multi vestibule release. But it is not the main strategy of the system. Remember we talk about actually, there are two type of the hair cells. Why is the inner hair cell? Why is outer hair cell? Which hair cells responsible for the sound perception in the hair cell, right? In the hair cell, actually will transfer signal through the axon, actually through the brain, but the other hair cell does not. When the hair cell receives the input from the brain. This is really quite strange. Why should the sensory cell need to receive the brain input? Actually people have found is quite interesting, the outer hair cell, actually the mechanical change the length of the cell. When you have a sound simulation, that is actually the outer hair cell is so special. Yeah, you can take a look at these molecules. These molecules actually are expressed in this cell body of the hair cell. And this is a membrane protein.
