Molecular basis of neural activity

A primer on membrane potential, ion channels, and neurotransmitters.

Part I.

As you may have learned in your introductory biology classes in high school or college, the fundamental unit of the cell membrane is the lipid bilayer. A double leaflet of phospholipids, with their charged phosphate group pointing towards the aqueous inner and outer environments, and their nonpolar, hydrophobic tail groups clustered together, protected from water, the lipid bilayer is the perfect selectively permeable membrane - if a molecule is small enough, or nonpolar enough, it can simply float through the bilayer, but if it is too large, or highly polar or charged, it cannot pass without the aid of a specialized transmembrane protein. In this way the lipid bilayer forms a selectively permeable barrier - the cell can effectively choose what gets in and out and when. It's not hard to imagine that a cell needs many different types of transmembrane proteins specialized for the translocation of some species from one side of the membrane to the other. Some of the most basic, and most important of these are the ion channels and pumps. Together, these two types of proteins form the basis for many cellular processes, from blocking the entry of more than one sperm into an egg, to neurotransmission, muscle contraction, and exocytosis of vesicles containing hormonal signals. So, what are the basics?

1. Cells expend energy to establish and maintain a gradient of several ion species across the membrane. Your brain uses around 40% of your energy - and a large proportion of this energy is consumed by the Na/K ATPase, or sodium-potassium pump. This protein couples the breakdown of a molecule of ATP (the energy currency of the cell) to the transport of a few sodium ions out of the cell and a few potassium ions in. The result of this transporter's action is that sodium ions are present in higher concentration outside the cell, and potassium ions are present in higher concentration on the inside. Calcium is also higher out than in, though cells may also sequester calcium inside membrane-bound organelles such as endoplasmic reticulum, or sarcoplasmic reticulum in muscle cells.

2. Cell membranes hold an electrical gradient as well. The interior of the cell contains a number of negatively-charged species, such as phosphate groups and organic acids. In terms of classical E&M physics, the cell membrane acts as a capacitor, storing up charge without allowing it to pass. The extracellular sodium ions are strongly attracted to the negative inner membrane surface and build up along the membrane, making the extracellular face of the membrane highly positively charged. This adds up to a potential gradient across the membrane of around -70 mV in most cells. By convention, this number is negative when the intracellular environment is more negative than the extracellular.

3. By controlling the flux of ions across the membrane, a cell can harness the drive of cations to flow into the cell. Ligand-gated and voltage-gated ion channels are the two most important classes of transmembrane transporters that allow ions to flow down an electrochemical gradient and to be harnessed for intracellular signalling. Ligand-gated ion channels, those which are opened by the binding of a particular small molecule such as dopamine, open in the presence of neurotransmitters and allow sodium and (to a smaller extent) calcium ions to flow into the cell. Voltage-gated ion channels of many different types open and close at certain membrane potentials, forming the basis of the action potential, the fundamental unit of neural activity.

In summary, the ionic basis for neurotransmission can be thought of in terms of an equation straight out of high school physics: V=IR, or I=V/R. I, or current, is the flux or net movement of charged particles; in our case, it's the flow of ions across a membrane. V, or voltage, represents the gradient across the membrane. This gradient has two components: chemical and electrical. A higher concentration of sodium ions outside than in, combined with a negatively charged intracellular environment, in effect form two forms of "motivation" for a sodium ion to cross the membrane. R, or resistance, can be thought of as the path by which a species can cross the membrane. Ions are far too big and charged to cross the membrane without the assistance of a channel; without a channel present, R is very high (if not infinite), so no matter what V is, there is no I or current. The presence or opening of channels across the membrane lowers the resistance, thus increasing the current.

OK, that's enough for today. Next time I'll try to get into the mechanics of an action potential, and the roles of voltage-gated sodium and potassium ion channels. As always, wikipedia is a great place to learn more. Here's the article on lipid bilayers, in case you want to know more.

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