Neurotransmitters: The nervous system


In our nervous system, the nerve impulse is transfers through neuron, the neuron accept signal from other neuron, integrate the information and then transfer the signal to other cells. Neurons communicate with each other at a specialized junction called synapse. Synapse is a structure that enables the neuron to pass electrical or chemical signal to another neuron or other cells like muscle cell. According to Groves and Rebec (1992), synapse is a tiny gap or cleft that can be found between the presynaptic membrane that send information and postsynaptic membrane that receive the information. According to Levy, Koeppen and Stanton (2006), there are different types of synapses such as axodendritic, axosomatic, axoaxonal and dendrodendritic.

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Basically, these synapses can be classified into electrical and chemical synapses. Electrical synapse transfers the current through an intercellular channel, the gap junction. The structure of gap junction allows passive transfer of the current whereby the action potential is generated due to the fluctuations in postsynaptic potential (Purves et al., 2004). As discussed by Purves et al. (2004), the chemical synapse involves the release of neurotransmitter from the presynaptic membrane to postsynaptic cell as the space between the pre- and post-synaptic neurons is much bigger than that for electrical synapse. Claiming that the action potential can be transmitted from one membrane directly to the other, Synapses (2004) stated that nerve impulse is allowed to be transmitted in a faster speed in electrical synapse as compared to the chemical synapse. However, this type of synapses is found only in the heart and eyes (Synapses, 2004). Most of the neurotransmitters can be categorized into major chemical class of amino acids, oligopeptides, and amines. For example, the acetylcholine that mediates the transmission between motor neuron and skeletal muscle cell, autonomic nervous system and the central nervous system.

The transfer of synapse is recognized as one way conduction in which the synapse impulse only pass through the presynaptic membrane toward the postsynaptic membrane and it will never happen in the reverse direction as the receptor of neurotransmitter can only be found on the postsynaptic membrane (Levy et al., 2006).

Components involve in the signal transmission at synaptic cleft

Synapse contains synaptic cleft, neurotransmitter, synaptic vesicle, presynaptic membrane and postsynaptic membrane. There are 5 types of synapse: excitatory ion channel synapses, inhibitory ion channel synapses, non-channel synapses, neuromuscular junctions and electrical synapses. Excitatory ion channel synapses consists of sodium channels as neuroreceptors while inhibitory ion channel synapses have chloride channels as the neuroreceptors (Synapses, 2004). Unlike the other synapses, non-channel synapses comprise of membrane-bound enzymes instead of channel to be the neuroreceptor. When the neurotransmitters bind to the receptor, a series of chemical reaction will be triggered inside the cell. These synapses are usually involved in slow and long-lasting responses. Neuromuscular junctions are the synapses the found between motor neurons and muscle cells connecting the nervous system to muscular system.

Synaptic vesicles contain neurotransmitters which function as a storage and carrier of neurotransmitter to be diffused out from the presynaptic membrane by exocytosis (Sudhof & Rizo, 2011). Synaptic cleft is the space of the small gap between one axon terminal of nerve cell and the dendrite of another nerve cell. Since the electrical nerve impulse cannot transmit the signal through synaptic cleft, neurotransmitter is needed to carry this nerve impulse to next neuron. Neurotransmitters are the brain chemicals that communicate and transmit information throughout our brain and body. According to Best (2014), there are three major classes of neurotransmitter, namely peptides, monoamines and amino acids. There are 2 types of neurotransmitters: inhibitory and excitatory. Inhibitory neurotransmitters include serotonin, gaba and dopamine (Neurogistics, 2014). Excitatory neurotransmitters include dopamine, norepinephrine and epinephrine.

Process of signal transmission
1. Generating action potential

Transmission of electrical impulse starts at the brain where electrical impulse is generated. The electrical impulse generated in the brain is then travelled along the nerve cell, known as axon to be transported to the other parts of the body for a specific reaction to occur. Brain generates electrical impulses when it is stimulated by external factor such as heat, pressure, sound and so on.

When neuron is not firing any electrical impulses, it is said to be at rest (Hall, 1998). When it is at rest, the neuron maintains an electrical polarization, which means the electrical potential that exists inside the neuron’s membrane is negative to the outside of the neuron’s membrane. This difference in electrical potential is known as resting potential (The Neuron, 2004). At rest, the electrical potential is approximately -65 mV. During resting potential, the concentration of Sodium (Na+) ions outside of the neuron’s membrane is higher than that of the inside while Potassium (K+) ion is more concentrated inside the neuron’s membrane compared to the outside (The Neuron, 2004).

Detection of stimulus will cause the cell membrane to depolarize past the threshold value which then resulting in the opening of voltage-activated Na+ gates and subsequently allow sodium ions to enter into neuron (Hall, 1998). The inflow of sodium ion caused the membrane potential to depolarize from -65 mV to +50mV which is the highest amplitude of the action potential (Hall, 1998). The voltage-activated Na+ gates are closed while the K+ gates are opened wider than usual for the K+ ion to flow out of the neuron past the resting potential when the highest action potential is achieved (The Neuron, 2004).

After action potential, the concentration of Na+ ions is higher while the concentration of K+ ions is lower in the neuron for a short period of time (Hall, 1998). This situation is then adjusted by the sodium-potassium pumps, allowing the concentration gradient of neuron to go back to resting potential. There is a refractory period following right after an action potential occurred (The Neuron, 2004). This is the recovery time where the neuron will not be able to produce subsequent action potential immediately and to ensure that the action potential only moves in one direction (The Neuron, 2004).

2. Signal transmission at synaptic cleft
2.1. Binding of neurotransmitter to the membranes

Synaptic delay happens in synaptic cleft. Synaptic vesicles enclosing neurotransmitters are found abundantly docking at the active zones of the presynaptic membrane (Levy et al., 2006). Opening of voltage-gated calcium ions channels upon the detection of action potential causes the influx of calcium ions. Subsequently, synaptic vesicles bind to the plasma membrane of presynaptic cells and neurotransmitter is released into synaptic cleft by exocytosis. The released neurotransmitters act as the chemical synapse after they enter the synaptic cleft.

These neurotransmitters bind to ligand-gated ion channels or receptors on the postsynaptic membrane. Lodish et al. (2000) mentioned that chemical synapse can be classified as excitatory or inhibitory depending on the action towards action potential at postsynaptic neuron. Binding of neurotransmitters to the receptors on the postsynaptic membrane leads to temporary changes in the membrane potential.

Once the binding of neurotransmitter to receptor shows temporary depolarization, it is termed as excitatory postsynaptic potential (EPSP) and is considered as excitatory chemical synapse (Levy et al., 2006). Excitatory chemical synapse opens channels that allow the influx of positively charged sodium and potassium ions so that the postsynaptic neuron is depolarized to generate action potential (Lodish et al., 2000). Thus, the action potential produced generates electrical response at the postsynaptic neuron. On the contrary, inhibitory chemical synapse shows inhibitory postsynaptic potential (IPSP) when the postsynaptic neuron exhibits transient hyperpolarization after the binding of neurotransmitter to its receptor (Levy et al., 2006). Channels that allow the influx of negative ions such as potassium ions and chloride ions are opened when neurotransmitter binds to the inhibitory receptor (Lodish et al., 2000). Hence, hyperpolarization occurs and action potential is inhibited.

2.2. How neurotransmitters are removed from synaptic cleft

After neurotransmitters bind with the receptors and transmit signals to post-synaptic neuron, they must be released from the receptors and removed from synaptic cleft to terminate the postsynaptic potentials which can continuously stimulate the post-synaptic cell. There are three important ways to terminate post-synaptic signaling, which are diffusion, re-uptake, and enzymatic degradation.

Neurotransmitters can be removed from synaptic cleft through a simple mechanism which is diffusion. After neurotransmitters are dissociated from the receptors, they move away from synaptic cleft and they can no longer bind to the receptors. Re-uptake is another mechanism important for terminating post-synaptic signaling. Pre-synaptic membrane has special transporters molecules embedded in it and they can pump the neurotransmitters back into the pre-synaptic neuron from synaptic cleft. Norepinephrine, dopamine, and serotonin can be removed from synaptic cleft through this mechanism. Serotonin transporter (SERT) and other biogenic amine transporters are dependent on sodium (Na+) and chloride (Cl) ions (William College Neuroscience, 1998).

Acetylcholine (ACh) can be inactivated via enzymatic degradation by acetylcholinesterase (AChE). Active site of AChE consists of two subunits which are important for breakdown of ACh. The anionic site of AChE is important to bind ACh to enzyme and the esteratic subsite is responsible to break the ester bond of ACh to release choline and acetate (William College Neuroscience, 1998). Choline is provisionally trapped in the folds of muscular endplate or is directly pumped back into pre-synaptic neuron via high affinity choline uptake (HACU) system (William College Neuroscience, 1998). Recycled choline can be used for synthesizing new ACh. Acetate is covalently bonded to serine residue at esteratic subsite forming enzyme-bound intermediate (William College Neuroscience, 1998; Lodish et al., 2000). Acetate group is released after a water molecule is reacted with the intermediate and an active enzyme which can react with another ACh is formed (William College Neuroscience, 1998).

3. Postsynaptic node
3.1. Signal transmission to the postsynaptic node

The neurotransmitters from the presynaptic cell membrane migrate through the synaptic cleft and binds with receptor channel membranes that can be found at postsynaptic membranes where these channels are chemically gated. Synaptic Transmission (n.d.) states that the amount of time taken for neurotransmitter to travel from presynaptic cell membrane to the receptor on postsynaptic cell membrane is less than a millionth of a second.

The receptor channels that serve as a binding site for neurotransmitter can be differentiated into direct and indirect receptor channel. The neurotransmitter after binding with the direct receptor channel or ionotropic receptor will cause conformational changes thus allowing ions to pass through the postsynaptic cell membrane (Synaptic Transmission, n.d.). Indirect receptor channel or metabotropic receptor coupled to G proteins is where the binding of receptor channel with neurotransmitter causes the secretion of a chemical molecule called secondary messenger (Synaptic Transmission, n.d.). The secondary messenger then activates nearby ion channels indirectly. Metabotropic receptor is a more common type of postsynaptic channel but it is considerably slower where the process takes place between 30 milliseconds to 1 second (Synaptic Transmission, n.d.). In Excitatory Postsynaptic Potentials (EPSP), the ion channels are permeable to both Na+ and K+ ion (Synaptic Transmission, n.d.). More Na+ ions travel into the cell due to the electrical concentration gradient. This result in the cells becoming more positive and local depolarization occurs until it reaches the electrical threshold thus generating an action potential. Inhibitory ion channels are permeable to both Cl and K+ ions. Cl ions move into the cell whereas K+ ions move out of the cell because of the concentration gradient where inside of the cell is more positive. The influx of Cl ions will cause the inside of cell to become more negative resulting in hyperpolarization (Synaptic Transmission, n.d.).

3.2. Signal transmission to muscle cells

Skeletal muscles are effector organs used in the locomotor system (Hopkins, 2006). Nerve impulses travel along the motor neuron and arrived at the motor end plate. The neurotransmitters (acetylcholine) are released from the synaptic vesicles at the neuromuscular junction (Lee, 2010). The acetylcholine diffuses across the synaptic cleft and depolarizes the sarcolemma of skeletal muscle (Lee, 2010). The depolarisation takes place then leads to the production of an action potential when the threshold level is exceeded (Hopkins, 2006). The action potential travels along the sarcomere and the wave of depolarisation spread down to the invaginations in the sarcomere, called the T-transverse tubules (Lee, 2010). The skeletal muscle action potential triggers the release of Ca2+ from the sarcoplasmic reticulum into the sarcoplasm and the presence of Ca2+ promotes the formation of actin-myosin bridges that finally causes muscle contraction (Levy et al., 2006). The increased cytosolic Ca2+ ions bind to the troponin complex that is associated with the tropomyosin (Lee, 2010). The troponin changes its shape and position, exposing the myosin binding sites on the actin filament. The myosin head of the thick filament will binds to the myosin binding sites on the actin filament creating an actin-myosin bridge and undergoes power stroke to complete a sliding filament model of muscle contraction. After the action potential ends, Ca2+ ions are transported back into the calcium vesicles to be stored in the sarcoplasmic reticulum (Lee, 2010). As the cytosolic Ca2+ decreases to its normal concentration, troponin and tropomyosin shifted back to their original shapes and positions (Bio301, n.d.). Once the tropomyosin back to its original position, the exposed myosin binding sites are blocked again and muscle will relax.

3.3. The difference between the mechanism of signal transmission in nerve cell and muscle cell

The difference between synaptic transfer to postsynaptic nerve cell (intermediate pathway in nerve impulses) and muscle cell (end pathway of nerve impulse) is the target tissue of neurotransmitter. Acetylcholine released induces depolarization in postsynaptic nerve cell in continuous transmission whereas depolarization happened at sarcolemma cells of skeletal cells for terminal transmission. In normal nerve impulses, the action potential travel along the neuron cells but in muscle cells, the action potential travel along the t-tubules to release Ca2+ for subsequent process that eventually lead to muscle contraction.

Malfunction of synaptic cleft

Sieber (2010) stated that glutamate is an important excitatory neurotransmitter found in the brain’s synapse. Glutamate-filled vesicles will be docked at a particular area of the presynaptic membrane which is known as active zone and they will diffuse through the synaptic cleft and stimulate the subsequent cell in the chain by interacting with the receptor proteins. The glutamate binds to postsynaptic glutamate receptors and induces an ionic influx whereby the neuron will become depolarized (Farooqui, Ong, & Horrocks, 2007).

Elevated level of glutamate will cause excitotoxicity whereby the neurons will be overstimulated and results in neuronal dysfunction and cell death. This situation will cause osmotic imbalance whereby the cell membranes will eventually burst when it is countered by the influx of Na+, CI and water. Sieber (2010) stated that when the level of glutamate increases excessively, it will cause the jamming of a nerve cell in an open position and thus permitting the calcium to flow freely into the cells through the AMPA and NMDA receptor channels and also through the voltage-dependent Ca2+ channels. Mattson (2003) stated that excessive calcium influx will results in the activation of apoptosis. Excitotoxic cascades will take place in the postsynaptic dendrites as the concentration of glutamate receptors are the highest in this region. The synapses will be locally degenerated and plasticity will occur as a result of the cascade. Subsequently, the signals will be propagated to the cell body and causes cell death (Mattson, 2003).

The occurrence of excitotoxicity will lead to neurodegenerative disease such as Alzheimer’s disease, Hungtinton disease and Parkinson’s disease (Dong, Wang, & Qin, 2009). Nerve cells are unable to be repaired when they are damaged and the patient will have permanent impairments (wiseGEEK, n.d.).

Drugs Interrupt Neurotransmission

According to National Institutes of Health (2010), drugs will affect neurotransmission in the way of disturbing the activity of neurotransmitter at the synaptic cleft. As a whole, the drugs can be classified into two major types depend on the interruption caused by drug at the synapses. The one which stimulates synapse is known as agonists while another one which inhibits synapse activity is named as antagonist (“Drug”, 2013).

Drugs alter the neurotransmission by affecting the release of dopamine into synaptic cleft. The examples of drugs which have this effect include alcohol, heroin, and nicotine. The effect is initiated when the dopamine-containing neurons in the ventral tegmental area (VTA) is activated (National Institutes of Health, 2010). Once the excitation of dopamine-containing neurons happens, indirectly, the action potential that will further stimulate the release of dopamine at synapse will elevate (National Institutes of Health, 2010).

Another type of effect which caused by drugs is the secretion of neurotransmitter regardless of the stimulation of impulse (National Institutes of Health, 2010). For instance, the presence of amphetamines in synapse causes the liberation of dopamine from vesicles independent of the action potential strength (Nordqvist, 2011). Succinylcholine drug causes the desensitization of sarcoplasmic reticulum (Walter & Emile, 2011). The conformation of succinylcholine drug is almost similar to acetylcholine and it possesses higher affinity and longer effect on the receptor. Some drugs like cocaine and amphetamines prevent the reuptake of neurotransmitter from synaptic cleft into presynaptic neuron (National Institutes of Health, 2010).

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