Ion channels are remarkable proteins, present in the lipid bilayer membrane of both animal and plant cells and their organelles, such as nucleus, endoplasmic reticulum, Golgi apparatus, mitochondria, chloroplasts, and lysosomes.
When we google the word “ion channel,” about 80,000,000 results pop up within 0.45 s. Scientists have been working on these amazing transmembrane proteins since the beginning of the last century, which has resulted in three sets of Nobel prizes in 1963, 1991, and 2003.
Sir John Carew Eccles, Alan Lloyd Hodgkin, and Andrew Fielding Huxley in 1963 received Nobel Prize for Physiology and Medicine for their discoveries concerning the ionic mechanisms involved in excitation and inhibition in the peripheral and central portions of the nerve cell membrane [1, 2]. Similarly, Erwin Neher and Bert Sakmann in 1991 proved that cell membranes have individual ion channels through which tiny currents can pass, which are big enough to generate communications between pre- and postsynaptic neurons by converting chemical or mechanical events into electrical signals [3, 4]. The Nobel Prize in Chemistry for 2003 was shared between two scientists Agre  and Roderick MacKinnon  who have made fundamental discoveries concerning how water and ions move through cell membranes.
In this book, we have
In the following pages of Chapter 1, we will be looking at the role of gating in ion channels for the maintenance of normal physiology and how any of these alterations in the gating result in the channelopathies.
Before going any further, we would like to acknowledge the sculpture called the birth of an idea. It is a 1.5-m tall figurine of KcsA potassium channel, made up of wires and blown glass, representing the channel’s lumen [7, 8]. This statue was commissioned to Julian Voss-Andreae by Nobel Prize winner Roderick Mackinnon.
There are three main types of ion channels, i.e., voltage-gated, extracellular ligand-gated, and intracellular ligand-gated along with two groups of miscellaneous ion channels. These ion channels are responsible for the transmission of signals between nerve and other types of electrically active cells [9, 10] through synapses and gap junctions [11, 12]. Alterations in the electrical potential of presynaptic neurons initiate the release of neurotransmitters from the vesicles in the synaptic cleft . These chemicals move toward the postsynaptic cells through the diffusion and occupy their specific receptor sites on membranes and generate the electrical potential by opening ion channels . Removal of neurotransmitters from the synaptic cleft is essential to avoid any effect on the nearby cells [14, 15, 16]. Cell signaling by neurotransmitters is far more adaptable and versatile as compared to the gap junctions .
2. Distinctive features of ion channels and ion transporter proteins
More than 106 ions are transported in a second through the ion channels without the help of metabolic energy like ATP, cotransport, or the active transport mechanism . There are two types ion channels, nonselective or large pore and selective (archetypal) or small pores [19, 20]. Ions typically pass through the channel pores in the form of a single file almost as fast as they move through a free solution. In most of the ion channels, the passage across the pores is governed by a “gate.” The gate may be opened or closed in response to different factors such as: electrical signals, chemical signals, temperature, and the mechanical force [14, 15, 18]. In summary, ion channels are the integral membrane proteins which are usually present as assemblies of many subunit proteins [16, 19]. In most voltage-gated ion channels, α subunit is the pore-forming subunit, while β and γ are the auxiliary subunits .
2.1. Diversity and classification of ion channels
There are many different types of ion channels distributed in each cell of our body; for example, in the cells of inner ear alone, there are about 300 ion channels . Ion channels are mainly classified [23, 24] on the basis of the following:
The nature of gating;
The types of ions passing through the said gates;
The number of the gates.
2.1.1. Classification by gating
Ion channels could be classified on the basis of gating, i.e., type of stimuli responsible for their opening and closing. Electrical gradient across the plasma membrane are responsible for the opening and closing of voltage-gated ion channels [25, 26]; however, binding of the ligands to the channels is responsible for the activation and deactivation of ligand-gated ion channels .
These channels are also known as the ionotropic receptors and get opened in response to specific ligand molecules binding to the extracellular domain of the receptor proteins [28, 29, 30]. Binding of the ligand causes a conformational change in the channel protein that ultimately leads to the opening of the channel gate and subsequent ion flux across the plasma membrane occurs [31, 32]. Cation-permeable “nicotinic” acetylcholine receptors, ionotropic glutamate-gated receptors, acid-sensing ion channels (ASICs), ATP-gated P2X receptors, and the anion-permeable γ-aminobutyric acid-gated GABA receptors are a few examples of ligand-gated channels [29, 31, 33].
188.8.131.52. Other gating
Activation and inactivation of ion channels by second messengers are included under this heading. Some examples are:
Genetic and autoimmune disorders of the ion channels cause channelopathies. If a mutant gene encodes an ion channel protein that is present on the cell membrane of heart, muscles, or brain, it results in the development of diseases in these organs [34, 35]. For example, if a gene encoding Na+ channel is mutated, then the protein for that channel will be defected and will be incapable to function properly; for example, in myotonia, there is delayed muscle relaxation after voluntary contraction. The abnormal Na+ channels are not able to deactivate, thus initiating repeated membrane depolarizations and resultant muscle contractions. Similarly, abnormality of the K+ and Ca2+ channels in the brain can cause epilepsy. The repeated nerve firings result in convulsions and fits, known as epileptic seizures . Generally, the cell repolarization is effected due to a defect in the voltage-gated ion channels such as K+, Ca2+, Cl−, and Na+. Similarly, any impediment in the Nav can lead to hyperkalemic periodic paralysis [36, 37]. Stress, alarm, or strenuous activity can stimulate paramyotonia congenital (PC), potassium-aggravated myotonia (PAM), generalized epilepsy with febrile seizures plus (GEFS₊), and episodic ataxia (EA), marked by acute bouts of extreme discoordination with or without myokymia [36, 37]. Similarly, familial hemiplegic migraine (FHM) and spinocerebellar ataxia are due to mutation in one or more of the 10 different genes encoding the potassium channels, which also causes a ventricular arrhythmia syndrome called the Long QT syndrome. This mutation ultimately affects the cardiac repolarization . Another type of ventricular arrhythmia is caused by the mutations in genes coding for the voltage-gated sodium channels, and is known as the Brugada syndrome. Likewise, a mutation in the CFTR gene, which encodes for the chloride channel, causes cystic fibrosis .
Defect in the transient receptor potential cation channel, mucolipin subfamily (TRPML1) channel, due to a mutation in any of its genes results in mucolipidosis type IV [34, 40, 41]. Some very vital events occur in the cancer cells due to the mutations and overexpression of genes encoding the ion channels; for example, glioblastoma multiform is marked by an increase in the number of receptors for glioma big potassium (gBK) channels and the CIC-3 chloride channels enabling the glioblastoma cells to move within the brain causing the diffuse growth patterns of these tumors.