Using linear estimates for non-linear processes.

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Re: Using linear estimates for non-linear processes.

Postby BioWizard on October 28th, 2015, 3:19 pm 

neuro » 28 Oct 2015 10:37 am wrote:Bio, in general you study ion channels by two procedures:
1) inject current into a cell, while measuring its membrane potential, and modulate the current in such a way that the membrane potential remains at the value you decide (voltage clamp): under this condition, the current across all membrane ion channels exactly equals the current you inject into the cell (otherwise the membrane potential would change), so you actually measure such cellular currents
2) inject current into a cell according to a precise paradigm (no current, or a current square wave, or a sinusoid, or whatever) and measure the ensuing changes in membrane potential (current clamp).

To study a specific kind of ion channels, you usually design a voltage clamp protocol:
1) a "holding" membrane potential is imposed to the cell: a certain fraction of the channels will typically be open at that potential (possibly none, e.g. no "delayed rectifier K channels" open at membrane potential <-70 mV);
2) from that holding potential you impose momentary steps (square waves of an appropriate duration) to a series of different "command" potentials.

Each specific type of voltage-dependent ion channels will give rise to a current, in response to each command pulse: such current will have a rising and possibly a falling phase, or maintain a steady value, and such kinetic properties will enable you to recognize the contribution of the specific type of channels you are interested in.

The pharmacological action of a drug can then be tested to examine whether it interferes, and to what extent, with the probability of being open for each channel type at any given membrane potential value (and possibly with the kinetics of channel opening-closing). For example, TEA is indeed a dirty drug, but it blocks the different kinds of K channels (IKV, the purely voltage-dependent component of outward rectifier K current or IKD; IKCa, the voltage and calcium-dependent component of IKD; IA, the rapidly activating and rapidly inactivating voltage dependent K current...) at very different concentrations. At low concentrations, it rather specifically blocks IKCa channels. This was a fortunate coincidence for us because it enabled us to develop the experimental protocol I discussed above


That answers all my questions. Thanks neuro.
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Re: Using linear estimates for non-linear processes.

Postby BioWizard on October 29th, 2015, 4:07 pm 

Natural ChemE » 27 Oct 2015 08:02 pm wrote:BioWizard,

In all seriousness, I'm going to print out a bunch of copies of that article on heavy paper (like resume paper), roll them up, and start bonking people on the head with it. I've got a whole slew of it in my office closet here now.


:]

I knew you'd like it. Ironically, I came across it totally independently of this discussion. We're developing a discovery pipeline and I was looking up some reports on biomedical research reproducibility/translatability in order to justify the (somewhat atypically) nuanced protocols we're proposing to do (I'm a lot more interested in actually getting something to the clinic than in just publishing papers). Then I stumbled across this one and though, oh! Well isn't this a convenient. I have several others but this one seemed so sweetly short, straightforward, and didn't seem to require much domain-specific knowledge in order to understand the sheer reality of the described problems.
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