Cell-cell communications

Gap junctions are formed by two juxtaposed rings, hexamers of the polypeptide connexin.

When these rings join, the form a channel, a connexon, between the adjacent cells.

Gap junctions are found in a wide range of cell types. The channel they form allows small, < 1000 daltons, molecules to pass from cell to cell.

It permits neighboring cells to share energy, ATP, and other small molecules.

The gap junction is regulated . If one cell is damaged, the gap junctions it makes with neighboring cells will close. This keeps damage to one cell from spreading and damaging its neighbors.

Gap junctions are involved in coordinating groups of cells. For example, cardiac muscle cells, cardiomyocytes, beat due changes in intracellular ion concentrations - specifically Ca²⁺ concentration.

Ca²⁺ ions can pass through gap junctions, and so groups of cells will beat in unison.

Cells can be coordinated through such calcium waves.

This is a simple type of informational junction.

A number of mutations in connexin genes lead to human disease, including deafness. Reorganization of gap junctions is also seen in heart disease.

Neuronal signaling

More complex adhesive/signaling junctions, known as synapses, lie between neurons and their targets.

That the nervous system is composed of discrete cells, as opposed to a syncitial network, was resolved by Santiago Ramon y Cajal.

He shared the Nobel prize with Camillo Golgi in 1906

Cajal was also responsible for many of foundations of neuroanatomy.

Neurons are highly differentiated, post-mitotic cells. Each type of neuron has a characteristic, and often highly stereotyped morphology.

In a generic neuron, signals are picked up by the dendritic arbor.

The incoming signals are integrated in the soma and can lead to signals that travel down the axon and into the terminal arbor.

The terminal processes make contact with the dendritic arbors of other neurons, or other target cell types.

The complexity of the connections between neurons can be rather overwhelming. There are neurons in the average human nervous system. A single large neuron, like one of the Purkinjie cells of the cerebellum, can have as many as 200,000 contacts with other neurons.

The basics of neuronal signaling

We will begin with the generation of an action potential, which is based on ion gradients across the plasma membrane.

Remember how the ATP synthase used the energy stored in H⁺ gradients to generate ATP? Now we will used the energy stored in ATP to generate Na⁺, K⁺ and Ca²⁺ ion gradients.

The enzyme Na⁺,K⁺ ATPase generates an ion gradient by pumping Na⁺ out of the cell and K⁺ into the cell.

At rest, the average neuron has a low internal [Na⁺] and a high internal [K⁺]; outside the cell [Na⁺] is high and [K⁺] is low.

Set the external voltage to zero and wait for the ions to equilibrate across the membrane.

Click on the link to start

Now turn on the external voltage, what happens?

The neuronal membrane is actually slightly permeable to K⁺ due the presence of a K⁺ leak channel.

In the resting state K⁺ diffuses down its concentration gradient, moving out of the cell. The membrane is impermeable to Na⁺ and so it cannot move to compensate. An electric field is generated.

K⁺ diffusion continue until the electric field generated, the membrane potential, is sufficient to oppose the [K⁺] gradient.

At the resting membrane potential, the net flux of K⁺ across the membrane is 0.

In most neurons, the resting membrane potential is ~-70 mV.

How, you might ask how can the membrane be permeable to K⁺ but not to Na⁺? Isn't K⁺ larger than Na⁺

You will of course remember that ions in water are associated with water molecules, their hydration shell. This alters their effective size.

Click on the image for a neat flash movie.

In addition to the K⁺ leak channel, the axonal and terminal membranes contain another protein, the voltage-gated Na⁺ channel.

At rest this channel is closed. As the membrane potential becomes less negative, or depolarized, there is a point known as the threshold potential when the voltage-gated Na⁺ channels open.

The voltage-gated Na⁺ channels carry much more current than the K⁺ leak channel.

Na⁺ moves down its concentration gradient until an electric potential is generated that opposes this movement -- the membrane potential will approach +50mV.

But this is a different closed state that the original one, it is refractory to opening and will not open again until it is reset.

The channel is reset only after the membrane has returned to the resting potential.

Once the Na⁺ channel is closed, current will be carried by the K⁺ channels only. The membrane will repolarize to the resting membrane potential.

The movement of this wave of electrical activity, the action potential, is normally unidirectional.

There are no voltage-gated Na⁺ channels in the dendritic arbor or soma.

Voltage-gated Na⁺ channels are present in the axon and the axonal hillock, where the axon exists the soma.

In this region, if the sum of all activity on the soma and dendrites leads to membrane depolarization above threshold, an action potential will start.

Information is encoded in the rate at which action potentials are fired.

The rate at which an axon can generate action potentials is dependent upon the speed at which it can reset its Na⁺ channels.

The key feature of the action potential is its an all or none self-regenerating behavior. This enables a neuron to transmit information over very long distances and without significant noise.

Some neurons are directly couple to their targets by gap junctions.

This is to referred to as an electrotonic synapse. The depolarization of one cell passes directly into the target cell.

Alternatively, there can be a gap between the terminal process and its target cell.

As the action potential invades the presynaptic region, it induces the opening of voltage-gated Ca²⁺ channels.

As intracellular [Ca²⁺] increases, it promotes the fusion of synaptic vesicles with specific docking sites, known as active zones, on the presynaptic membrane -- releasing neurotransmitter into the cleft.

The transmitter diffuses across the synaptic cleft and binds to neurotransmitter receptors on the surface of the post-synaptic cell.

The effects of the neurotransmitter on the post-synaptic cell depend upon the nature of the receptor.

There are three generic types of neurotransmitter receptors:

1. ligand-gated channels
2. G-protein linked receptors
3. enzyme-linked receptors.

The receptor and downstream signaling components determine the cell's response to a particular neurotransmitter.

Take, for example, acetylcholine

Nicotinic acetylcholine receptors in skeletal muscle are ligand-gated Na⁺ channels.

The binding of acetylcholine leads to depolarization, increase in intracellular [Ca²⁺] and muscle contraction.

Muscarinc acetylcholine receptors in cardiac muscle, are G-protein coupled receptors; their activation leads to the activation of various enzymes and the relaxation of the muscle cell.

The response of the target cell ends when release of the neurotransmitter stops and the neurotransmitter is either destroyed or removed.

Acetylcholine, for example, is hydrolyzed into acetate and choline by the enzyme acetylcholine esterase.

These are recycled by the presynaptic neuron to generate more acetylcholine.

A number of pesticides and nerve gases work by inhibiting acetylcholine esterase activity. If acetylcholine degradation is blocked, the muscle continues to contract and paralysis ensues.

Botulinum toxin, on the other hand, acts to block acetylcholine release by the presynaptic cell.

By activating different types of receptors a neurotransmitter can be excitatory, that is it can promote the firing of action potentials, or inhibitory, it can suppress the firing of the post-synaptic cell.

The output of a cell will be determined by the

• type of synapse that are made upon it
• where these synapses are located and
• the pattern of presynaptic firing activity.

The post-synaptic neuron integrates the various presynaptic inputs and outputs the result as a pattern of action potentials.

This network of interactions can be disrupted by toxins and disease.

Tetanus toxin, for example, acts by inhibiting inhibitory interneurons that regulate muscle contraction.

Once inhibited, all muscle begin to contract simultaneously, leading to spasm and death.

Tetrodotoxin, from the pufferfish, acts by blocking the voltage-gated Na⁺ channel.

The pattern of connections and activity within the nervous system determines the output of the system. Consciousness, in this view, is simply the product or output of complex neural networks.

These networks are not static however. Neurons can alter their connections with time and experience.

Why are computer's not conscious, perhaps because even though they are fast, their internal connections are actually quite simple, compared to a brain.