I. Introduction

Our nervous system regulates myriad of tasks in our organisms, from muscle movement and blood vessel dilation to thinking, learning, and our emotions. Each task is assigned to a circuit of neuronal cells which receive and dispatch the signals. Despite the complexity of the tasks and abundance of the neuronal pathways, the underlying molecular machinery is fairly uniform throughout the whole system. The signal within the cell is carried as action potential–a positive charge traveling along the neuron. The signal is then passed onto another neuron via release of small chemicals called neurotransmitters into intraneuronal space. These small molecules stimulate neighboring cells by binding to appropriate receptors. Once the message is passed, the neurotransmitters have to be quickly removed from the space between neurons to stop stimulating the target cells. Some types are transported back into the cell, some of them are destroyed by special enzymes.

Positively-charged sodium and potassium ions are the signaling agents that carry signals down the long axons of nerve cells. This happens in several steps. First, the sodium-potassium pump (Figure 1C) transfers sodium outside the cells, and potassium inside the cell. This along with other molecules and atoms creates a voltage gradient across the cell membrane (of -70 mV), which is used to power the fast transmission of the nerve signal. This state is refered to as "resting potential" and the membrane is said to be polarized (Figure1).

When the cell is triggered to send a signal, voltage-gated sodium channels (Figure 1A) open in the area near the start of the axon. This allows sodium ions to enter the cells, changing the voltage across the membrane to about +40 mV. This triggers more channels further along the axon to open, changing the voltage there, depolarizing the membrane. This wave of channel opening, termed the "action potential", sweeps down the axon.

Soon after, voltage-gated potassium channels (Figure 1C) in the area also open, allowing potassium ions to leave the cell, stopping the action potential. Once the voltage inside reaches about -75mv they close and the membrane is said to hyperpolarized. During this brief period another action potential cannot be triggered.

The membrane is restored to its -70mV resting potential value thanks to special potassium channels that allow the potassium to travel back inside the cell. Finally, the sodium-potassium pump begins transferring the sodium back out and the potassium back in, making the axon ready for another signal.

1. Neurotransmitters

Once the action potential reaches the terminal region of the neuron, called the synapse (Figure 2A), the signal is passed onto the next neuron (termed the “postsynaptic neuron”) by the release of neurotransmitters. These chemical messengers are small molecules or short peptides, stored in synaptic vesicles. When the action potential arrives, these vesicles fuse with the neuronal membrane, releasing neurotransmitters into the synaptic cleft. Once released, the neurotransmitters bind to matching receptors on the postsynaptic membrane (Figure 2B). There are many different neurotransmitters used for different jobs: glutamate excites nerves into action, GABA inhibits the passing of information, dopamine and serotonin are involved in the subtle messages of thought and cognition, and acetylcholine carries signals from nerve cells to muscle cells.

Glutamate

GABA

Dopamine

Serotonin

Acetylcholine

2a. Ionotropic Receptors

The ionotropic receptors, also called ligand-gated ion channels, contain an ion channel that opens upon neurotransmitter binding allowing the ions to flow through the channel. This event is very short and ions only flow for as long as the neurotransmitter is bound to the receptor. Once the neurotransmitter detaches, the receptor goes back to its closed confirmation. Depending on the type of neurotransmitter used and the receptor, they create inhibitory or excitatory postsynaptic potentials.

For example, an excitatory postsynaptic potential is created through glutamate interacting with AMPA receptor. Upon glutamate binding, the receptor channel opens to allow entry of positively-charged sodium, potassium, and calcium ions. The incoming ions depolarize the membrane, generating an action potential that travels down the neuron.

Inhibitory postsynaptic potential is created, for example, when GABA interacts with the GABA_A receptor. Upon GABA binding, the receptor allows the influx of negatively charged chloride, which hyperpolarizes the membrane, making it more difficult to start a new action potential.

Some neurons in our nervous system have synapses with both neurons sending excitatory signals and neurons sending inhibitory signals. The positive charge entering the neuron from the excitatory signal can be offset by the negative charge from the inhibitory neuron signal. In such cases, no action potential can be generated and the signal is halted. In this way, the neuron integrates the different inputs from many neurons, only sending a new signal when enough excitatory signals are received.

2b. Metabotropic Receptors

Metabotropic receptors, also called G-protein coupled receptors or GPCRs, activate signal transduction pathways upon neurotransmitter binding. All GPCRs have similar structure composed of a bundle of seven alpha helices that span the membrane. The helices form a cavity on the extracellular side where the neurotransmitters bind.

On the intracellular side, the receptors are coupled to G-proteins. G-proteins consist of alpha (Gα), beta (Gβ), and gamma (Gγ) subunits. When inactive, they have GDP bound to the Gα subunit. Ligand binding induces a conformational change in the receptor that leads to the activation of the G-protein. Upon activation, the GDP is released and GTP binds instead and the complex splits into 2 parts: Gα and Gβγ, which interact with other proteins in the signalling pathways.

There are several classes of Gα subunits depending on which protein they interact with. The stimulatory (Gαs) and inhibitory Gα (Gαi) interact with adenylyl cyclase–an enzyme that is responsible for production of the cyclic AMP (cAMP). Gαs stimulates cAMP production while Gαi inhibits the process. cAMP binds to some ion channels directly allowing ions to enter or exit the cell thus modulating the membrane voltage. cAMP is also used to activate channels indirectly via binding to CAMP dependent protein kinases, which in turn bind to other channels stimulating ion traffic.

Notice that the same neurotransmitter can mediate both excitatory and inhibitory neurotransmission, depending on the receptor it interacts with. For example, there are 5 types of dopamine receptors which are distributed in different areas of the brain: D1, D2, D3, D4, and D5. They modulate different pathways relating to tasks like locomotions, memory, attention, impulse control, sleep, etc. The D1 and D5 receptors activation stimulates production of cAMP while the activation of D2, D3, and D4 inhibit it ¹.

3. Stopping the signal: neurotransmitter removal

The neurotransmitters usually bind to their receptors for a short time. Once the signal is underway, they detach from the receptors and move freely in the synaptic cleft. To stop them from stimulating the receptors again, our nervous system employs special proteins to either transport them back into the pre-synaptic cell or to destroy them.

3a. Reusing neurotransmitter through transporters

Neurotransmitter transporters are small proteins found in the presynaptic membrane. They transport the neurotransmitter back into the presynaptic neuron, where they are repackaged into vesicles and used when needed.

3b. Destructing neurotransmitter through special enzymes

Some neurotransmitters are destroyed by special enzymes. For example, the excitatory neurotransmitter acetylcholine is disposed of by acetylcholinesterase. This neurotransmitter is synthesized inside the neurons from acetate and choline and interacts with acetylcholine receptors. The cholinergic neurons (neurons using mainly acetylcholine in communication) play critical role in memory, learning, and attention. In the synapses between nerve cells and muscle cells, acetylcholine triggers the process of muscle contraction. After its job is done, acetylcholinesterase breaks it back into acetyl and choline.