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Na/K ATP-ase Reversal

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Na/K ATP-ase Reversal

Postby rogelio » Wed Feb 21, 2007 3:27 am

A hypothetical situation in which the A and B proteins on the channel were reversed (A on outside now and B on inside) is proposed, and my prof. said that this setup would result in Oubain (cardiac glycoside) being ineffective because it only works on the B portion (which it can't get to because it's now inside).

However... Vanadate only works on the A portion (and prevents ATP phosphorylation)... so wouldn't the normal set-up of A inside and B outside be ineffective to Vanadate unless it is injected (uptaken) into the cell?

Also... he said in the "reversed" hypothetical question that K had to be inside the cell and Na outside for ATP hydrolysis (when it's ocurring outside the cell) is this just because the initial step requires Na+ pumping into the cell in reversed order to initiate phosphorylation?
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Postby Dr.Stein » Wed Feb 21, 2007 7:26 am

I am not sure with your question but I tried to tell this, maybe can explain you something:

Normally, more Na+ can be found outside the cell, whereas more K+ can be found inside the cell. Both Na+ and K+ have channel, which is voltage-gated. When there is an adequate stimulus, Na+ channel will open and the ion will start to flow inside the cell. At some point, adequate stimulus will open K+ channel, then this ion will start to flow outside the cell. This is passive facilitated transportation because the movement is along the concentration gradient.

When at the outside of the cell has too much K+ and inside the cell has too much Na+ (for instance in hyperpolarization period), Na/K ATPase pump will be activated to bring 2 K+ inside and force 3 Na+ outside (repolarization period). This pump is active transport, which need energy (ATP). This pump works because channels are closed and cannot be opened without adequate stimulus.
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Postby MrMistery » Wed Feb 21, 2007 4:41 pm

Doc i think you kinda missed the point..

Ok, here is how i would see the situation. Basically what you are doing is hypothetically taking the protein and putting it inside out right?
Well, in that case, if you still have the same concentrantion of ions into the cell as usual(more Na on the outside, more K on the inside) then after you make your switch of proteins the Na/K pump will run in reverse, ions will move down their concentration gradient and ATP will be formed. This is normal, as the Na/K, like any enzyme, can run in both ways. And yes, i agree that if you want it to hydrolyse ATP then you need to reverse the ion concentrations as well.

Your profesor is right. Digitoxigenine and oubaine only act on the B chain, and because there is no permease for these molecules, they cannot get inside the cell to bind with the B chain now.

But about vanadate.. Ar you sure it only binds to the A portion? Because if that is so, then yes, it would be ineffective unless somehow transported inside the cell. I have been searching my books for the mode of action of vandate and can not seem to find it. But common sense tells me that it needs to be inside the cell to compete with phosphate for the binding site. In this case, it would work great with your enzyme now.
As i know, vanadate inhibits every protein that binds phosphate, being highly similar, and of course the Na/K pump as well. However, because it needs to enter the cell it can not be used in vivo(does the cell have a mechanism to transport phosphate ions inside the cell? I think not but if anyone knows?!?!). My guess is professors just like to give the example of vanadate in order for students to realise that the Na/K pump is an enzyme with similar methods of function to others etc etc. For selective inhibition in vivo we use digitalis, which consists of digitoxine mostly.

I hope this helps in any way.
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Postby MrMistery » Wed Feb 21, 2007 4:43 pm

oh by the way vanadium is toxic for humans, the only animals that incorporate it in large amounts are some urochordates... ALthough i have no idea what they do with it.
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Postby Dr.Stein » Thu Feb 22, 2007 7:53 am

MrMistery wrote:Doc i think you kinda missed the point..

I told you before :P
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Postby Revenged » Sat Feb 24, 2007 10:47 pm

this is a bit of a side track from the original topic... but as cardiac glycosides were mentioned, i just wondered how effective they really are...

i mean, i thought the whole point of angina that oxygen supply doesn't meet demand... and that the physiological mechanisms make the heart work harder and make the angina worse... so you treat the angina by reducing the physiological responce and so you reduce work of the heart... so that oxygen consumption meets demand...

so you can prevent the heart working as hard... e.g. beta blockers (reduce b1 adrenoreceptor activation), nitric vasodilators (venous dilation, reduce preload), calcium receptor antagonists (e.g. verapamil reduced afterload)...etc.

but cardiac glycosides like digoxin increase heart workload... doesn't this make angina worse in the long run?... and what about the risks of cardiac arrhymias with the drugs... doesn't it make taking them risky?
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