Chapter 2:  Cells and within cells

Cells

Translation

Receptor Mechanisms

    Neurons

   Proteins, Protein Structure and Protein Analysis

    Glia

   Epigenetics

   Protein folding in the cell

Within cells

   Transcription

   Post-translational modifications of proteins

   Noncoding RNAs

   Protein degradation in the cell - Autophagy

   Membranes and Membrane Proteins

   miRNAs and the brain

   Protein secretion / Secretory pathway

   The Exctracellular Matrix

A quote from two eminent electrophysiologists in the study of ion channels:

"Our ability to do gymnastics, to perceive a colorful world, and to process language relies on rapid communication among neurons. Such signaling, the fastest in our bodies, involves electrical messages produced as ion channels in cell membranes open and close. Various ion channels mediate sensory transduction, electrical "computations", propagation over long distances, and synaptic transmission."

A general overview will be given of ion channels, what they are and what they do.

Ion channels are membrane bound proteins which allow ions to flow into or out of cells. They are usually constructed from 4 or 5 different protein subunits. These subunits form a ring the center of which is an ion pore. Shown here is an ion channel on the membrane constructed from individual subunits. The arrow is showing the pore through which ions will flow if the channel is open.

Ion channels in action 

There are two major classes of ion channels, those that are induced to open through the binding of a ligand and those that are induced to open by a change in membrane potential. The first group are referred to as ligand-operated or ligand-gated ion channels. The second group are referred to as voltage-operated or voltage-gated ion channels. On the right is a side view through the middle of a ligand-operated channel. The ligand (green circle) binds to specific sites in extracellular side of the ion channel. As a consequence of this binding "gates" deep within the receptor are induced to open and thus ions can flow through the channel. Ligands are usually small molecules neurotransmitters such as acetylcholine, glutamic acid or gamma aminobutyric acid (GABA).

For the second major class of ion channels, the voltage operated channels, there are no ligand binding sites. Rather, these ion channels possess voltage sensors (structure with positive charges in figure to left). With membrane depolarization (yellow arrows) the voltage sensors move and, in doing so, induce opening of an ion gate on the intracellular side of the channel. Ions are now free to flow into or out of the cell (in this example the channel is a Na+ channel and thus Na+ flows into the cell).

Ion channels are constructed from discrete proteins called "subunits". Voltage-operated channels are generally constructed from 4 subunits whereas ligand-operated ion channels are constructed from 5 subunits. Shown is a representation of voltage-operated and ligand-operated channels where each subunit is represented by a cylinder in the lipid bilayer (blue circles and red tails represent phospholipids of the bilayer). By  looking straight down on the channel, depicted on the far right, you can get an impression of the size of the pore (indicated as white circle). Note that because the ligand-operated channel has more subunits its pore is  larger than that of a voltage-operated channel. Because of the larger pore the ligand-operated channel is, in general, less ion specific that the voltage-operated channel. For example, one of the very important ligand-operated ion channels is the so-called NMDA receptor. This receptor is a Ca2+ channel but a considerable amount of Na+ also enters the cell via the receptor when the channel has opened.

Specificity and direction of ion flow 

                                                    Ion channels are usually quite specific for the ion which they allow to pass through the pore. Thus we speak of Ca²⁺ channels, Na⁺ channels, K⁺ channels and Cl^- channels. Ion specificity is largely determined by ion filters constructed within the channels. The direction an ion goes (into or out of the cell) depends on the so-called electrochemical equilibrium point for the ion. The electrochemical equilibrium  takes into account both the concentration gradient and the charge of the ion. The ion will flow into or out of the cell until it reaches its electrochemical equilibrium point. To explain further it is important to remember that a cell normally has a resting potential of between -50 to -70 mV. Thus, positive charges tend to be pulled into the cell and negative charges pulled out (this is the "electro" part of the electrochemical equilibrium point). However, for the K⁺ ion the concentration of the ion is far higher in the cell than outside and thus, with opening of a K⁺ channel the ion flows out. This is why it is important to consider both the charge and the concentration (i.e. the electrochemical equilibrium point of the ion) when deciding which way an ion will travel. Shown below are the usual directions of flow for various ions (the intensity of the colors gives an impression of the concentration gradients between the extracellular (top) and intracellular (bottom) compartments.

Opening of Ca²⁺ and Na⁺ channels cause the cell to become less negative inside, thus a depolarization and an activation of the cell. Opening of K⁺ and Cl^- channels cause the cell to become more negative inside, thus a hyperpolarization and an inhibition of the cell. Note that the Cl^- ion, like the K⁺ ion, travels with the chemical gradient and against the electro-gradient. In some cells the electrochemical equilibrium point for Cl^- is such that Cl^- flows in fact out of the cell (against the concentration gradient!) In this case opening of the Cl^- channel  leads to a depolarization and activation of the cell rather than the  normal hyperpolarization and inhibition of the cell. This again illustrates the importance, for each cell, to consider the electochemical equilibrium point and not just the concentration gradient of an ion when considering what the ion will do when the ion channel opens.

How is the resting potential achieved? 

What keeps ions from slowly diffusing (leaking) to their electrochemical equilibrium point and thus the cell loosing its resting membrane potential? The answer, nothing!...... and thus the cell must be constantly pumping ions to maintain the electrochemical gradients.  As an example, consider Na⁺ and K⁺, the two ions that make the most important contribution in determining the membrane potential. Na⁺/K⁺ ATPases are constantly active in the membrane, pumping 3 Na⁺ ions out for every 2 K⁺ ions in (red and blue circles respectively in figure to left). This already makes the inside of the cell more negative than the outside (3 + charges pumped out for every two + charges pumped in). Additionally, there are so-called "K⁺ leak channels" on the membrane which allow some of the K⁺ ions to leak out (down the electrochemical gradient). This leakage makes the cell even more negative inside and thus we arrive at a rest potential of -50 to -70 mV. All this pumping costs energy, energy derived from ATP-hydrolysis. Thus, the name for this pump is  Na⁺/K⁺-ATPase.