Wednesday, January 13, 2010

Thinking about Mechanisms (Part 2): The Depolarisation Mechanism

This post is part of my series on the work of the philosopher Carl Craver. The series deals with neuroscientific explanations. For an index, see here.

I am currently looking at an article entitled "Thinking About Mechanisms", published in the journal Philosophy of Science in 2000. Although authored along with two other philosophers of science, this article provides a valuable introduction to the main contours of Craver's work.

In part 1, I introduced two examples of biological mechanisms (Chemical Neurotransmission and DNA replication) and outlined a formal definition of a mechanism. This definition was as follows:
Mechanisms are entities and activities organised such that they are productive of regular changes from start, or set-up, to finish, or termination.
In this part, I take a more detailed look at the mechanism for chemical neurotransmission and see how the formal analysis applies to it.


The Mechanism of Chemical Neurotransmission
Chemical neurotransmission involves the conversion of an electrical signal in a presynaptic neuron (action potential), into a chemical signal in the synapse. This chemical signal is converted back into an electric signal in the postsynaptic neuron.

There are many stages to this process: (i) first there is a depolarisation of the presynaptic neuron; (ii) then an influx of Calcium ions into the presynaptic neuron; (iii) then there is a series of chemical reactions which transport vesicles of neurotransmitter to the membrane of the neuron; (iv) then the neurostransmitter is released into the synaptic cleft; (v) then the neurotransmitter diffuses across the synaptic cleft; and (vi) finally the neurotransmitter binds to receptor proteins in the postsynaptic cell.

This is an incredibly complex sequence of events, about which a great deal is known. It is far more complex than my summary suggests. Indeed, that summary is only an isolated snapshot of what goes on. But isolated snapshots are the essence of mechanistic explanations.

To grasp this point, and to consider in more depth how the formal definition of mechanisms applies to chemical neurotransmission, we will look solely at the first stage in the process outlined above: the depolarisation of the presynaptic neuron. This is its own sub-mechanism within the larger mechanism of chemical neurotransmission.


The Depolarisation Mechanism
In their resting states, neurons are electrically polarised. That is: the fluid inside the neuron is negatively charged with respect to the fluid outside the neuron (-70mV). This is referred to as the resting membrane potential. Depolarisation is a positive change in membrane potential.

There are three parts to the description of any mechanism: (i) the set-up conditions; (ii) the intermediate activities; and (iii) the termination conditions. They illustrate the descriptive adequacy of the formal definition of a mechanism that was provided earlier. Let's look at each of these parts in the case of the depolarisation mechanism.

(i) The Set-up Conditions
We begin with an idealised description of the entities (and their properties) that make up the mechanism. The description is idealised in that it is represented as being static. In the depolarisation mechanism, the set-up conditions include:

  • The overall structural properties and spatial locations of the entities.
  • The differential intra and extra-cellular concentrations of Na+.
  • The location of the alpha helix protein in the ion-channel. This protein is a string of evenly-spaced positively charged amino acids.
  • The hairpin turn in the protein making up the ion channel. This has a particular configuration of positive and negative charge that becomes important in the intermediate activities.
  • Background conditions (held constant) such as temperature, pH, and the presence or absence of pharmacological agonists or antagonists.
These set-up conditions are illustrated in the diagram below (click to enlarge).




(ii) The Intermediate Activities
Having grasped the set-up conditions we can look to see what goes on during the intermediate activities. The entities participate in these activities and they jointly produce the termination conditions of the mechanism. In the case of the depolarisation mechanism, the intermediate activities can be broken down into four parts:

  • The action potential, which is an electrical signal traveling down the neuron towards the synapse, spreads some Na+ ions through the interior of the cell. They repel the positive charge in the alpha helix voltage gates.
  • The alpha helices are thus rotated about their axes, thereby opening a channel through the membrane.
  • These changes in protein structure contort the hairpins such that they now line the channels.
  • This makes the channel selective for Na+ ions that are outside the cell and these ions are transported into the neuron.
This stage is illustrated below.



(iii) Termination Conditions
The final part of a mechanistic explanation is an idealised description of the termination condition. In other words: a static description of the changed status of the entities from the set-up conditions.

In the case of the depolarisation mechanism, the termination conditions are easily described: there is an increase in intracellular Na+ concentrations and a corresponding increase in membrane voltage.

This is illustrated below.




So there you have it, a more detailed look at a mechanistic explanation in action. In the next part, we will examine some of the more philosophical questions that arise from these explanations.

2 comments:

  1. Thank you for sharing this series. This subject is not something on which I am really at all knowledgable, and I enjoy learning new information about it. Please keep up the good work. I enjoy all of your ongoing series.

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  2. ditto to teleprompter -- well written -- awaiting the next installment !

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