Action Potential

For a long time, the process of communication between nerves and their target tissues was largely unknown to physiologists. With the development of electrophysiology and the discovery of the electrical activity of neurons, it was discovered that signal transmission from neurons to their target tissues is mediated by action potentials. An action potential is defined as a sudden, rapid, transient, and propagating change in the resting membrane potential. Only neurons and muscle cells are capable of generating an action potential; that property is called excitability.


Action potentials are nerve signals. Neurons generate and conduct these signals throughout their processes to transmit them to target tissues. Upon stimulation, they will be stimulated, inhibited, or modulated in some way.


But what causes the action potential? From an electrical aspect, it is caused by a stimulus with a certain value expressed in millivolts [mV]. Not all stimuli can cause an action potential. The appropriate stimulus must have sufficient electrical value to reduce the negativity of the nerve cell to the threshold of the action potential. Thus, there are subthreshold, threshold and suprathreshold stimuli.

  • Subthreshold stimuli cannot cause an action potential.
  • Threshold stimuli have enough energy or potential to produce an action potential (nerve impulse).
  • Suprathreshold stimuli also produce an action potential, but its strength is greater than that of threshold stimuli.
  • So, an action potential is generated when a stimulus changes the membrane potential to threshold potential values. The threshold potential is usually between -50 and -55 mV. It is important to know that the action potential behaves according to the law of all or nothing. This means that any subthreshold stimulus will not cause anything, whereas threshold and suprathreshold stimuli produce a full response from the excitable cell.

Is an action potential different depending on whether it is caused by a threshold or suprathreshold potential? The answer is no. The length and amplitude of an action potential are always the same. However, increasing the strength of the stimulus causes an increase in the frequency of an action potential. An action potential propagates along with the nerve fibre without diminishing or weakening its amplitude and length. Also, after an action potential is generated, neurons become refractory to stimuli for a certain period of time where they cannot generate another action potential.


From the point of view of ions, an action potential is caused by temporary changes in the permeability of the membrane for diffusible ions. These changes cause the ion channels to open and the ions to decrease their concentration gradients. The value of the threshold potential depends on the permeability of the membrane, the intracellular and extracellular concentration of ions, and the properties of the cell membrane.

An action potential has three phases: depolarization, overshoot, and repolarization. There are two more states of the membrane potential related to the action potential. The first is hyperpolarization that precedes depolarization, while the second is hyperpolarization that follows repolarization.

Hyperpolarization is the initial increase in membrane potential to the value of the threshold potential. The threshold potential opens voltage-gated sodium channels and causes a large influx of sodium ions. This phase is called depolarization. During depolarization, the interior of the cell becomes increasingly electropositive, until the potential approaches the electrochemical equilibrium for sodium of +61 mV. This phase of extreme positivity is the overdrive phase.

After the overshoot, the permeability to sodium suddenly decreases due to the closure of its channels. The overshoot value of the cell potential opens voltage-gated potassium channels, causing a large outflow of potassium, which lowers the electropositivity of the cell. This phase is the repolarization phase, the purpose of which is to restore the resting membrane potential. Repolarization always leads first to hyperpolarization, a state in which the membrane potential is more negative than the default membrane potential. But soon after, the membrane re-establishes the values ​​of the membrane potential.

After reviewing the functions of the ions, we can now define threshold potential more precisely as the value of the membrane potential at which voltage-gated sodium channels open. In excitable tissues, the threshold potential is about 10 to 15 mV lower than the resting membrane potential.

Refractory period

The refractory period is the time after an action potential is generated, during which the excitable cell cannot produce another action potential. There are two subphases of this period, absolute and relative refractoriness.

1. Absolute refractoriness overlaps depolarization and about 2/3 of the repolarization phase. A new action potential cannot be generated during depolarization because all voltage-gated sodium channels are already open or are opening at their maximum rate. During early repolarization, a new action potential is impossible since the sodium channels are inactive and need the resting potential to be in a closed state, from which they can return to an open state. Absolute refractoriness ends when enough sodium channels recover from their inactive state.

2. Relative refractoriness is the period in which the generation of a new action potential is possible, but only in response to a suprathreshold stimulus. This period overlaps the final 1/3 of repolarization.

Propagation of the action potential.

An action potential is generated in the body of the neuron and propagates down its axon. Propagation does not diminish or affect the quality of the action potential in any way, so the target tissue receives the same impulse no matter how far away it is from the cell body.

The action potential is generated at a point on the cell membrane. It spreads across the membrane, and each succeeding part of the membrane depolarizes sequentially. This means that the action potential does not move but instead elicits a new action potential from the adjacent segment of the neuronal membrane.

We need to emphasize that the action potential always propagates forward, never backward. This is due to the refractoriness of the parts of the membrane that were already depolarized, so the only possible direction of propagation is forward. Because of this, an action potential always propagates from the cell body, down the axon to the target tissue.

The speed of propagation depends largely on the thickness of the axon and whether or not it is myelinated. The larger the diameter, the higher the rate of propagation. Propagation is also faster if an axon is myelinated. Myelin increases the speed of propagation because it increases the thickness of the fibre. Furthermore, myelin allows for saltatory conduction of the action potential, since only the nodes of Ranvier are depolarized and myelin nodes are skipped. In unmyelinated fibres, each part of the axonal membrane must undergo depolarization, which makes propagation significantly slower.


A synapse is a junction between the nerve cell and its target tissue. In humans, synapses are chemical, meaning that the nerve impulse is transmitted from the axon terminal to the target tissue by chemicals called neurotransmitters (ligands). If a neurotransmitter stimulates the action of the target cell, then it is an excitatory neurotransmitter. On the other hand, if it inhibits the target cell, it is an inhibitory neurotransmitter. Depending on the type of target tissue, there are central and peripheral synapses. Central synapses occur between two neurons in the central nervous system, while peripheral synapses occur between a neuron and muscle fibre, peripheral nerve, or gland.

Each synapse consists of:

  • Presynaptic membrane: membrane of the terminal button of the nerve fibre.
  • Postsynaptic membrane: membrane of the target cell.
  • Synaptic cleft: a gap between the presynaptic and postsynaptic membranes

Numerous vesicles containing neurotransmitters are produced and stored within the terminal button of the nerve fibre. When the presynaptic membrane is depolarized by an action potential, voltage-gated calcium channels open. This leads to an influx of calcium, which changes the state of certain membrane proteins in the presynaptic membrane and results in the exocytosis of the neurotransmitter in the synaptic cleft.

The postsynaptic membrane contains receptors for neurotransmitters. Once the neurotransmitter binds to the receptor, ligand-gated channels in the postsynaptic membrane open or close. These ligand-gated channels are the ion channels and their opening or closing will cause a redistribution of ions in the postsynaptic cell. Depending on whether the neurotransmitter is excitatory or inhibitory, this will result in different responses.


Biochemistry, study of the chemical substances and processes that occur in plants, animals, and microorganisms and the changes they undergo during development and life. It deals with the chemistry of life, and as such draws on the techniques of analytical, organic, and physical chemistry, as well as those of physiologists interested in the molecular basis of life processes. All chemical changes within the organism, whether it be the breakdown of substances, usually to obtain the necessary energy or the accumulation of complex molecules necessary for life processes, are collectively called metabolism.

These chemical changes depend on the action of organic catalysts known as enzymes, and enzymes, in turn, depend on their existence on the genetic apparatus of the cell. It is not surprising, therefore, that biochemistry enters the investigation of chemical changes in disease, drug action, and other aspects of medicine, as well as nutrition, genetics, and agriculture.

The term biochemistry is synonymous with two somewhat older terms: physiological chemistry and biological chemistry. Aspects of biochemistry that deal with the chemistry and function of very large molecules (eg, proteins and nucleic acids) are often grouped under the term molecular biology. Biochemistry is a young science, known under that term only since around 1900. However, its origins go back much further; its early history is part of the early history of both physiology and chemistry.

Study areas

A description of life at the molecular level includes a description of all the complexly interrelated chemical changes that occur within the cell, that is, the processes known as intermediary metabolism. The processes of growth, reproduction, and heredity, also subjects of biochemists’ curiosity, are intimately related to intermediary metabolism and cannot be understood independently of it. The properties and capabilities exhibited by a complex multicellular organism can be reduced to the properties of the individual cells of that organism, and the behaviour of each individual cell can be understood in terms of its chemical structure and the chemical changes that occur within that cell.

Chemical composition of living matter.

Every living cell contains, in addition to water and salts or minerals, a large number of organic compounds, substances composed of carbon combined with varying amounts of hydrogen and, usually, oxygen as well. Nitrogen, phosphorus, and sulfur are also common constituents. In general, most of the organic matter in a cell can be classified as (1) protein, (2) carbohydrate, and (3) fat or lipid. Nucleic acids and various other organic derivatives are also important constituents. Each class contains a great diversity of individual compounds. There are also many substances that cannot be classified in any of the above categories, although usually not in large quantities.

Proteins are essential to life, not only as structural elements (eg, collagen) and to provide a defence (as antibodies) against invading destructive forces, but also because the essential biocatalysts are proteins. The chemistry of proteins is based on the research of the German chemist Emil Fischer, whose 1882 work showed that proteins are very large molecules, or polymers, made up of about 24 amino acids. Proteins can range in size from small (insulin with a molecular weight of 5,700 (based on the weight of a hydrogen atom as 1)) to very large molecules with molecular weights of over 1,000,000.

The first complete amino acid sequence was determined for the insulin molecule in the 1950s. By 1963 the amino acid chain in the protein enzyme ribonuclease (molecular weight 12,700) had also been determined, with the help of the powerful physical techniques of analysis. of X-ray diffraction. In the 1960s, Nobel Prize winners JC Kendrew and M. F. Perutz, using X-ray studies, built detailed atomic models of the proteins haemoglobin and myoglobin (the respiratory pigment in muscle), which were later confirmed by sophisticated chemical studies. The continuing interest of biochemists in protein structure is based on the fact that the arrangement of chemical groups in space provides important clues about the biological activity of molecules.

Carbohydrates include substances such as sugars, starch, and cellulose. The second quarter of the 20th century saw a startling advance in understanding how living cells handle small molecules, including carbohydrates. Carbohydrate metabolism became elucidated during this period, and the elaborate pathways of carbohydrate breakdown and subsequent storage and utilization were gradually described in terms of cycles (eg, the Embden-Meyerhof glycolytic cycle and the Krebs cycle). ). The involvement of carbohydrates in respiration and muscle contraction was well elaborated in the 1950s. Refinements of the schemes continue.

Fats, or lipids, are a heterogeneous group of organic chemicals that can be extracted from biological material by nonpolar solvents such as ethanol, ether, and benzene. The classic work on the formation of body fat from carbohydrates was done in the early 1850s. Those studies, and subsequent confirmatory evidence, have shown that the conversion of carbohydrates to fat occurs continuously in the body. The liver is the main site of fat metabolism.

The absorption of fat in the intestine was studied as early as the 1930s. It is known that the control of fat absorption depends on a combined action of the secretions of the pancreas and bile salts. Abnormalities of fat metabolism, which give rise to disorders such as obesity and rare clinical conditions, are the subject of much biochemical research. Equally interesting to biochemists is the association between high levels of fat in the blood and the development of arteriosclerosis (“hardening” of the arteries).

Nucleic acids are large, complex compounds of very high molecular weight present in the cells of all organisms and in viruses. They are of great importance in the synthesis of proteins and in the transmission of hereditary information from one generation to the next. Originally discovered as components of cell nuclei (hence their name), it was assumed for many years after their isolation in 1869 that they were found nowhere else. This assumption was not seriously questioned until the 1940s, when it was determined that there are two types of nucleic acid: deoxyribonucleic acid (DNA), in the nuclei of all cells and in some viruses; and ribonucleic acid (RNA), in the cytoplasm of all cells and in most viruses.

The profound biological importance of nucleic acids gradually came to light during the 1940s and 1950s. Attention turned to the mechanism by which protein synthesis and genetic transmission were controlled by nucleic acids (see below, Genes). During the 1960s, experiments were aimed at refining the genetic code. Promising attempts were made in the late 1960s and early 1970s to replicate nucleic acid molecules outside the cell, that is, in the laboratory. By the mid-1980s, genetic engineering techniques had achieved, among other things, in vitro fertilization and DNA recombination (so-called gene splicing).

Evolution and origin of life.

Space exploration beginning in the mid-20th century intensified speculation about the possibility of life on other planets. At the same time, the man was beginning to understand some of the intimate chemical mechanisms used for the transmission of hereditary characteristics. By studying the structure of proteins in different species, it was possible to see how the amino acid sequences of functional proteins (for example, haemoglobin and cytochrome) have been altered during phylogeny (the development of species). It was natural, therefore, for biochemists to regard the problem of the origin of life as a practical one. The synthesis of a living cell from inanimate material was not considered an impossible task for the future.

Transposons Shifting Segments of the Genome

Transposable elements (TEs), which shift segments of the Genome are also known as “jumping genes”. These elements were first identified more than 50 years ago by geneticist Barbara McClintock of the Cold Spring Harbor Laboratory in New York. Biologists were initially sceptical of McClintock’s discovery. However, over the next several decades, it became clear that TEs not only “jump” but are also found in almost all organisms (both prokaryotes and eukaryotes), and usually in large numbers. For example, TEs constitute approximately 50% of the human genome and up to 90% of the maize genome (SanMiguel, 1996).


Unlike class 2 elements, class 1 elements, also known as retrotransposons, move through the action of RNA intermediates. In other words, class 1 TEs do not encode transposase; rather, they produce RNA transcripts and then rely on reverse transcriptase enzymes to reverse transcribe the RNA sequences back into DNA, which is then inserted into the target site.

There are two main types of class 1 TEs: LTR retrotransposons, which are characterized by the presence of long terminal repeats (LTRs) at both ends; and non-LTR TE, which lacks repeats. Both the LINE1, or L1, and Alu genes represent non-LTR TE families. L1 elements average about 6 kilobases in length. By contrast, Alu elements average only a few hundred nucleotides, making them a short interspersed transposable element, or SINE.

Alu is particularly prolific, originating in primates and expanding in a relatively short time to about 1 million copies per cell in humans. L1 is also common in humans; although it is not present in as many copies as Alu, its larger size means that this element constitutes approximately 15%-17% of the human genome (Kazazian & Moran, 1998; Slotkin & Martienssen, 2007). In humans, these non-LTR TEs are the only active class of transposons; LTR retrotransposons and DNA transposons are just ancient genomic relics and are not capable of hopping.

Autonomous and non-autonomous transposons

Both class 1 and class 2 TEs can be autonomous or non-autonomous. Autonomous TEs can move on their own, while non-autonomous elements require the presence of other TEs to move. This is because nonautonomous elements lack the transposase or reverse transcriptase gene needed for their transposition, so they must “borrow” these proteins from another element to move. Ac elements, for example, are autonomous because they can move on their own, while Ds elements are not autonomous because they require the presence of Ac to transpose.

What Jumping Genes Do (Besides Jumping)

The fact that about half of the human genome is made up of TEs, with a significant portion of the L1 and Alu retrotransposons, raises an important question: What do all these jumping genes do, besides jump? Much of what a transposon does depends on where it lands. Landing inside a gene can result in a mutation, as was discovered when L1 insertions into the factor VIII gene caused haemophilia (Kazazian et al., 1988). Similarly, a few years later, the researchers found L1 on the APC genes in colon cancer cells, but not on the APC genes in healthy cells in the same individuals. This confirms that L1 is transposed in mammalian somatic cells and that this element could play a causal role in disease development (Miki et al., 1992).

Silencing and Transposons

Unlike L1, most TEs appear to be silent; in other words, these elements do not produce a phenotypic effect nor do they actively move through the genome. At least that has been the general scientific consensus. Some silenced TEs are inactive because they have mutations that affect their ability to move from one chromosomal location to another; others are perfectly intact and capable of movement but are kept inactive by epigenetic defence mechanisms such as DNA methylation, chromatin remodelling, and miRNAs. In chromatin remodelling, for example, chemical modifications to chromatin proteins cause chromatin to shrink so much in certain areas of the genome that genes and TEs in those areas are silenced because transcription enzymes simply can’t access them.

Another example of transposon silencing involves plants of the genus Arabidopsis. Researchers studying these plants have discovered that they contain more than 20 different mutator transposon sequences (a type of transposon identified in maize). In wild-type plants, these sequences are methylated or silenced. However, in plants that are defective for one of the enzymes responsible for methylation, these transposons are transcribed. Furthermore, several different mutant phenotypes have been explored in methylation-deficient plants, and these phenotypes have been linked to transposon insertions (Miura et al., 2001).

Based on studies like these, scientists know that some ETs are epigenetically silenced; in recent years, however, researchers have begun to question whether certain TEs might have a role in epigenetic silencing. Interestingly, it was Barbara McClintock who first speculated that TEs might play this type of regulatory role (McClintock, 1951). Scientists have taken decades to collect enough evidence to consider that perhaps McClintock’s speculation had an ounce of truth.

Transposons can encode siRNAs that mediate their own silencing

Because transposon movement can be destructive, it is not surprising that most transposon sequences in the human genome are silent, allowing this genome to remain relatively stable, despite the prevalence of TE. In fact, the researchers believe that of the 17% of the human genome that is encoded by L1-related sequences, only about 100 active L1 elements remain. Furthermore, the research suggests that even these few remaining active transposons are inhibited from jumping in a variety of ways that go beyond epigenetic silencing.

For example, in human cells, small interfering RNAs (siRNAs), also known as RNAi, can prevent transposition. RNAi is a natural mechanism that eukaryotes often use to regulate gene expression. What is especially interesting about this situation is that the siRNAs that interfere with L1 activity are derived from the 5′ untranslated region (5′ UTR) of LTR L1. Specifically, the 5’UTR of the L1 promoter encodes a sense promoter that transcribes L1 genes, as well as an antisense promoter that transcribes antisense RNA. Yang and Kazazian (2006) showed that this results in homologous sequences that can hybridize, thus forming a double-stranded RNA molecule that can serve as a substrate for RNAi. Furthermore, when the researchers inhibited endogenous siRNA silencing mechanisms, they observed an increase in L1 transcripts, suggesting that L1 transcription is indeed inhibited by siRNA.

Transposons are not always destructive

Not all transposon jumping has harmful effects. Indeed, transposons may drive the evolution of genomes by facilitating translocation of genomic sequences, exon shuffling, and double-strand break repair. Insertions and transpositions can also alter phenotypes and gene regulatory regions. In the case of the medaka fish, for example, the DNA transposon Tol2 is directly related to pigmentation. A highly inbred line of these fish was shown to have a variety of pigmentation patterns.

In the members of this line in which the Tol2 transposon jumped “cleanly” (ie, without removing other parts of the genomic sequence), the fish were albino. But when Tol2 did not jump cleanly from the regulatory region, the result was a wide range of hereditary pigmentation patterns (Koga et al., 2006).

The fact that transposable elements are not always perfectly removed and can take up genomic sequences during the journey has also resulted in a phenomenon scientists call exon shuffling. Exon shuffling results in the juxtaposition of two previously unrelated exons, usually by rearrangement, potentially creating new gene products (Moran et al., 1999).

The ability of transposons to increase genetic diversity, coupled with the ability of the genome to inhibit most TE activity, results in a balance that makes transposable elements an important part of gene evolution and regulation in all organisms that carry these sequences.