3.2.2 Fundamentals of neurons and receptors

Fundamental Concepts in the Physiology of Neurons, Synapses and Receptors

The human brain consists of approximately 86 billion neurons, these communicate with each other through chemical signals or electrical signals. Neurons ‘communicate’ or are connected via the synapses. Synapses consist of the presynaptic and postsynaptic terminals. The presynaptic terminal exists at the end of the axon and is also where electrical signals are converted into chemical signals.

Neurotransmitters released from the presynaptic terminal and particular receptors on the corresponding postsynaptic terminal are critical in the transmission of information. The postsynaptic neuron receives the signals in order to interpret and determines the next step.

Neuron structure consists of a cell body, neuronal processes, axons and dendrites. Change occurs in the voltage flow of neurons from dendrites, and soma to the axon. Electrical signals pass through to the axon in the form of action potential so a nerve cell is able to communicate with another neuropathway. These communications are called synaptic transmission (Jones, 2017).

Parts of the neuron:

*Neuronal component:*	*Description:*
Cell body	The cell body consists of the nucleus which is the set of metabolic activity. Synapses are synthesized and it also releases neurotransmitters.
Dendrites	Dendrites are appendages that are designed to receive communications from other cells.
Axon	Axon is shaped like a cylinder covered by an axolemma, neurofilaments and microtubules give support to the axon. Neurotransmitters transport through microtubules from the cell body to the pre-synaptic terminal.
Synapses	Synapses are the site of transmission from the pre-synaptic neuron to the post-synaptic neuron.
Axo-dendritic	Communication between one neuron axon to the dendrites of other neurons. These are called excitatory synapses.
Axo-somatic	One neuron’s dendrites is connected with another neuron which is known as an inhibitor synapse.
Axo-axonic	The connection between the terminal of the two axons, these synapses work as a regulator role. Afferent axon work in the release of neurotransmitters from the end of efferent neurons. This is the most common pathway of communication from neuron to neuron and axon to axon. This frequently takes place in the central nervous system. Communication between neurons to other neuron signal termination is in the form of electrical current (Südhof, T.C., 2018).
Presynaptic	A presynaptic neuron transmits the signal toward a synapse.
Postsynaptic	A postsynaptic neuron transmits the signal away from the synapse.

(Südhof, 2012) (Südhof, 2018)

An Understanding of Resting Potential, Action Potential, Ion Fluxes and Channels

The resting potential, action potential, ion fluxes, and ion channels are all important concepts in understanding the behaviour of cells, particularly neurons. The resting potential represents the baseline voltage difference across the plasma membrane, while the action potential represents a rapid change in this voltage. Ion fluxes refer to the flow of ions into and out of a cell, driven by the voltage difference and the concentration gradient of each ion. Ion channels play a critical role in controlling ion fluxes by allowing specific ions to move into or out of the cell in response to changes in the voltage difference or in response to specific ligand binding. Understanding these concepts helps us to understand how cells, particularly neurons, transmit electrical signals and communicate with one another (Lisman, 2007).

Resting potential:

The resting potential is the voltage difference across the plasma membrane of a cell when it is not actively firing an action potential.
The typical resting potential in neurons is approximately -70 millivolts (mV).
The resting potential is maintained by a balance between positively charged ions (such as sodium, Na+) and negatively charged ions (such as chloride, Cl-) within and outside the cell. The concentration of potassium ions is much higher inside the cell compared to outside, and the concentration of sodium ions is much higher outside the cell compared to inside. This creates a concentration gradient for each ion.
The resting potential is maintained by the presence of ion channels that are selectively permeable to specific ions. For example, potassium ion channels allow potassium ions to move from high concentration inside the cell to low concentration outside the cell, thereby maintaining the negative charge inside the cell.

Action potential:

An action potential is a rapid and brief change in the voltage difference across the plasma membrane of a cell. This results in the rapid and brief flow of ions into and out of the cell.
Action potentials occur in response to a stimulus, such as the arrival of an electrical signal at the membrane of a neuron.
The change in voltage during an action potential is due to the opening of voltage-gated ion channels. Voltage-gated ion channels are specific types of ion channels that open or close in response to changes in the voltage difference across the plasma membrane.
During an action potential, voltage-gated sodium ion channels open and allow sodium ions to rush into the cell, leading to a rapid and brief change in the voltage from the resting potential to approximately +30 mV. This is followed by the opening of voltage-gated potassium ion channels, which allow potassium ions to rush out of the cell, leading to a return of the voltage to the resting potential.

Ion fluxes:

Ion fluxes refer to the flow of ions into and out of a cell.
Ion fluxes are driven by the voltage difference across the plasma membrane, as well as the concentration gradient of each ion.
The voltage difference across the plasma membrane creates an electrical gradient, which influences the flow of ions.
The concentration gradient of each ion influences the flow of ions. Ions will naturally move from high concentration to low concentration.
Ion channels play a critical role in controlling ion fluxes by allowing specific ions to move into or out of the cell.

Ion channels:

Ion channels are proteins that span the plasma membrane and control the flow of ions into and out of the cell.
There are several types of ion channels, including voltage-gated, ligand-gated, and mechanically-gated ion channels.
Voltage-gated ion channels are specific types of ion channels that open or close in response to changes in the voltage difference across the plasma membrane.
Ligand-gated ion channels are open or close in response to the binding of a specific molecule (ligand).
Mechanically-gated ion channels are open or closed in response to mechanical pressure or distortion of the plasma membrane.

An Understanding of G-protein Coupled Receptors, Allosteric Modulation of Receptors, Synaptic Plasticity and Pruning etc.

G-protein coupled receptors:

G-protein coupled receptors exist in a large amount in the body tissues. G-protein coupled receptors are receptor proteins that are coupled to intracellular G-proteins as transducing elements. They are referred to as metabotropic.

These are responsible for extracellular signals, which include neurotransmitters and also are responsible for generating intracellular signals. Molecular signal cascades are responsible for many different functions of the body. G-protein coupled receptors regulate our five senses such as vision, pain, taste, and smell.

G-protein coupled receptors play a vital role in recognition and communication. Many G-protein coupled receptors contain seven transmembrane α-helical domains. The amino end of the protein lies at the exterior of the plasma membrane. Loops of amino acids connect the helices either at the exterior surface or on the cytosolic surface of the membrane. The loops on the cytosolic side are helices 5 and 6 and are usually substantially longer than the others.

G-protein coupled receptors act via cyclase-mediated second messenger activation using ATP or GTP. G-protein coupled metabotropic receptors can influence protein synthesis and thus have the ability to cause long-standing effects.

Examples of G-protein coupled metabotropic receptors are:

Dopamine receptors
5HT receptors (except 5HT-3)
Neuroendocrine neoplasms and associated neuropeptides such as opioid receptors

Allosteric modulation:

An allosteric modulator is a set of substances that are attached to receptors to change the response of the receptors to a particular stimulus. Allosteric modulators are of three types named as positive, negative, and neutral. A positive allosteric modulator increases the probability by increasing the receptor’s response. In the negative type, agonist affinity or efficacy decreases. In neutral it restricts the modulator from binding to an allosteric site and agonist activity is not affected (Keov, 2011).

Plasticity and pruning:

Synaptic plasticity regulates the process of communication between two neurons. The communication strength of two synapses may be likened to the conversation volume. When neurons communicate with each other, this is done at a different level of volume, some neurons communicate slowly like whispering to other neurons and some communicate in a louder manner like shouting (Abbott, 2000).

Synaptic pruning is a process in which the brain eliminates extra synapses Synapses are the communication mediator of the brain that play a role in the transmission of electric and chemical signals to another neuron. Synaptic pruning is a process in which extra synaptic connections and neurons that are no longer needed are eliminated in order to enhance the efficiency of neuronal transmission (Chechik, 1998).

References:

(1) Abbott, L.F. and Nelson, S.B., 2000. Synaptic plasticity: taming the beast. Nature Neuroscience, 3(11), pp.1178-1183.

(2) Chechik, G., Meilijson, I. and Ruppin, E. (1998). Synaptic Pruning in Development: A Computational Account. Neural Computation, 10(7), pp.1759–1777. doi:10.1162/089976698300017124.

‌(3) Jones, R.A., Harrison, C., Eaton, S.L., Hurtado, M.L., Graham, L.C., Alkhammash, L., Oladiran, O.A., Gale, A., Lamont, D.J., Simpson, H. and Simmen, M.W., 2017. Cellular and molecular anatomy of the human neuromuscular junction. Cell reports, 21(9), pp.2348-2356.

(4) Keov, P., Sexton, P.M. and Christopoulos, A., 2011. Allosteric modulation of G protein-coupled receptors: a pharmacological perspective. Neuropharmacology, 60(1), pp.24-35.

(5) Lisman, J.E., Raghavachari, S. and Tsien, R.W., 2007. The sequence of events that underlie quantal transmission at central glutamatergic synapses. Nature Reviews Neuroscience, 8(8), pp.597-609.