INTRODUCTION:

Ion channels are pore-forming membrane proteins whose functions include establishing a resting membrane potential, shaping action potentials and other electrical signals by gating the flow of ions across the cell membrane, controlling the flow of ions across secretory and epithelial cells, and regulating cell volume. Ion channels are present in the membranes of all cells. Ion channels are one of the two classes of ionophoric proteins, along with ion transporters (including the sodium-potassium pump, sodium-calcium exchanger, and sodium-glucose transport proteins).[1,2]

Ion channels were firstly analysed by the British Biophysian CealanHodgkin and Andrew Huxley. They are awarded by the Nobel Prize for the research on action potential published in 1952 than in 1970 existence of ion channel were confirmed by Bernard Katz and Ricardo Miledi by using the noise analysis.

Figure-1: Transmembrane pore forming ion channel

1. Channel domain

2. Outer vestibule

3. Selectivity filter

4. Diameter of selectivity filter

5. Phosphorylation site

6. Cell membrane

BASIC FEATURES OF ION CHANNELS:

There are two main features of the ion channel which distinguish them from other types of ion transporter protein: The rate of ion transport through the channel is very high. (≥10, 00000ions per sec.) Ion passes through the channel according to the concentration gradient. [2]

Ion channels are located within the membrane of most cells and of many intracellular organelles. They are often described as narrow, water-filled tunnels that allow only ions of a certain size and/or charge to pass through. This characteristic is called selective permeability. The archetypal channel pore is just one or two atoms wide at its narrowest point and is selective for specific species of ion, such as sodium or potassium.

However, some channels may be permeable to the passage of more than one type of ion, typically sharing a common charge: positive (Cations) or negative (anions). Ions often move through the segments of the channel pore in single file nearly as quickly as the ions move through free solution.

In many ion channels, passage through the pore is governed by a "gate", which may be opened or closed in response to chemical or electrical signals, temperature, or mechanical force.Ion channels are integral membrane proteins, typically formed as assemblies of several individual proteins. Such "multi-subunit" assemblies usually involve a circular arrangement of identical or homologous proteins closely packed around a water-filled pore through the plane of the membrane or lipid bilayer.[3,4]

BIOLOGICAL ROLE OF ION CHANNELS:

Because channels underlie the nerve impulse and because "transmitter-activated" channels mediate conduction across the synapses, channels are especially prominent components of the nervous system. Indeed, numerous toxins those organisms have evolved for shutting down the nervous systems of predators and prey work by modulating ion channel conductance and/or kinetics. In addition, ion channels are key components in a wide variety of biological processes that involve rapid changes in cells, such as cardiac, skeletal, and smooth muscle contraction, epithelial transport of nutrients and ions, T-cell activation and pancreatic beta-cell insulin release. In the search for new drugs, ion channels are a frequent target [5, 6, 7]

Figure-2: Biological role of different receptors

CLASSIFICATION BY GATING:

Ion channels may be classified by gating, i.e. what opens and closes the channels. Voltage-gated ion channels open or close depending on the voltage gradient across the plasma membrane, while ligand-gated ion channels open or close depending on binding of ligands to the channel.

Voltage gated:

Voltage-gated ion channels are a class of transmembrane proteins that form ion channels that are activated by changes in the electrical membrane potential near the channel. The membrane potential alters the conformation of the channel proteins, regulating their opening and closing. Cell membranes are generally impermeable to ions, thus they must diffuse through the membrane through transmembrane protein channels. They have a crucial role in excitable cells such as neuronal and muscle tissues, allowing a rapid and co-ordinated depolarization in response to triggering voltage change. Found along the axon and at the synapse, voltage-gated ion channels directionally propagate electrical signals. Voltage-gated ion-channels are usually ion-specific, and channels specific to sodium (Na+), potassium (K+), calcium (Ca2+), and chloride (Cl–) ions have been identified.[1],[2] The opening and closing of the channels are triggered by changing ion concentration, and hence charge gradient, between the sides of the cell membrane[8]

Mechanism:

Voltage-gated sodium channels and calcium channels are made up of a single polypeptide with four homologous domains. Each domain contains 6 membrane spanning alpha helices. One of these helices, S4, is the voltage sensing helix. [9]The S4 segment contains many positive charges such that a high positive charge outside the cell repels the helix, keeping the channel in its closed state. In general, the voltage sensing portion of the ion channel is responsible for the detection of changes in transmembrane potential that trigger the opening or closing of the channel. The S1-4 alpha helices are generally thought to serve this role. In potassium and sodium channels, voltage-sensing S4 helices contain positively-charged lysine or arginine residues in repeated motifs.[10] in its resting state, half of each S4 helix is in contact with the cell cytosol. Upon depolarization, the positively-charged residues on the S4 domains toward the exoplasmic surface of the membrane.

Figure-3: Voltage gated ion channel

It is assumed that the first 4 arginine explanation for the gating current, moving toward the extracellular solvent upon channel activation in response to membrane depolarization. The movement of 10–12 of these protein-bound positive charges triggers a conformational change in the protein that opens the channel.[11]The exact mechanism by which this movement occurs is not currently agreed upon, however the canonical, transporter, paddle, and twisted models are examples of current theories.[8]Movement of the voltage-sensor triggers a conformational change of the gate of the conducting pathway, controlling the flow of ions through the channel.[12]The main functional part of the voltage-sensitive protein domain of these channels generally contains a region composed of S3b and S4 helices, known as the "paddle" due to its nature, which looks like to be a well-maintained sequence, interchangeable across a wide variety of cells and species. A similar voltage sensor paddle has also been found in a family of voltage sensitive phosphates in various species.[13] Genetic engineering of the paddle region from a species of volcano-dwelling archaebacteria into rat brain potassium channels results in a fully functional ion channel, as long as the whole intact paddle is replaced. This "modularity" allows use of simple and inexpensive model systems to study the function of this region, its role in disease, and pharmaceutical control of its behavior rather than being limited to poorly characterized, expensive, and/or difficult to study preparations. Although voltage-gated ion channels are typically activated by membrane depolarization, some channels, such as inward-rectifier potassium ion channels, are activated instead by hyperpolarization. The gate is thought to be coupled to the voltage sensing regions of the channels and appears to contain a mechanical obstruction to ion flow.[14]

While the S6 domain has been agreed upon as the segment acting as this obstruction, its exact mechanism is unknown. Possible explanations include: the S6 segment makes a scissor-like movement allowing ions to flow through, [15] the S6 segment breaks into two segments allowing of passing of ions through the channel,[11]or the S6 channel serving as the gate itself.[8] Inactivation of ion channels occurs within milliseconds after opening. Inactivation is thought to be mediated by an intracellular gate that controls the opening of the pore on the inside of the cell. This gate is modeled as a ball tethered to a flexible chain. During inactivation, the chain folds in on itself and the ball blocks the flow of ions through the channel [17] Fast inactivation is directly linked to the activation caused by intramembrane movements of the S4 segments, though the mechanism linking movement of S4 and the engagement of the inactivation gate is unknown.

DIFFERENT TYPES OF ION CHANNEL:

Sodium channels are integral membrane proteins that form ion channels, conducting sodium ions (Na+) through a cell's plasma membrane. [18] They are classified according to the trigger that opens the channel for such ions, i.e. either a voltage-change ("Voltage-gated", "voltage-sensitive", or "voltage-dependent" sodium channel also called "VGSCs" or "Na channel") or a binding of a substance (a ligand) to the channel (ligand-gated sodium channels).

Figure-4: Voltage gated Sodium channel

Voltage-dependent calcium channels (VDCCs):

This are the group of voltage-gated ion channels found in the membrane of excitable cells (e.g., muscle, glial cells, neurons, etc.) with a permeability to the calcium ion Ca2+.[19] These channels are slightly permeable to sodium ions, so they are also called Ca2+-Na+ channels, but their permeability to calcium is about 1000-fold greater than to sodium under normal physiological conditions.[20] At physiologic or resting membrane potential, voltage dependent calcium ion channels are normally closed. They are activated or opened at depolarized membrane potentials and this is the source of the "voltage-dependent" epithet. The concentration of calcium (Ca2+ ions) is normally several thousand times higher outside of the cell than inside. Activation of particular VDCCs allows Ca2+ to rush into the cell, which, depending on the cell type, results in activation of calcium-sensitive potassium channels, muscular contraction,[21]excitation of neurons, up-regulation of gene expression, or release of hormones or neurotransmitters. VDCCs have been immunolocalized in the Zona glomerulosa of normal and hyperplastic human adrenal, as well as in aldosterone-producing adenomas (APA), and in the latter T-type VDCCs correlated with plasma aldosterone levels of patients.[22]

Potassium channels:

Potassium channels are the largest and most diverse class of voltage-gated channels, with over 100 encoding human genes. These types of channels differ significantly in their gating properties; some inactivating extremely slowly and others inactivating extremely quickly. This difference in activation time influences the duration and rate of action potential firing, which has a significant effect on electrical conduction along an axon as well as synaptic transmission. Potassium channels differ in structure from the other channels in that they contain four separate polypeptide subunits, while the other channels contain four homologous domains but on a single polypeptide unit. [23]

Chloride ion channels:

Chloride channelsare a superfamily of poorly understood ion channels specific for chloride. These channels may conduct many different ions, but are named for chloride because its concentration in vivo is much higher than other anions. Several families of voltage-gated channels and ligand-gated channels (e.g., the CaCC families) have been characterized in humans.Voltage-gated chloride channels display a variety of important physiological and cellular roles that include regulation of pH, volume homeostasis, organic solute transport, cell migration, cell proliferation and differentiation. Based on sequence homology the chloride channels can be subdivided into anumber of groups.

Figure-5: Chloride ion channels

Voltage-gated proton channels:

Voltage-gated proton channels are ion channels that have the unique property of opening with depolarization, but in a strongly pH-sensitive manner.[14] The result is that these channels open only when the electrochemical gradient is outward, such that their opening will only allow protons to leave cells. Their function thus appears to be acid extrusion from cells.[24] Another important function occurs in phagocytes (e.g. eosinophils, neutrophils, and macrophages) during the respiratory burst. When bacteria or other microbes are engulfed by phagocytes, the enzyme NADPH oxidase assembles in the membrane and begins to produce reactive oxygen species (ROS) that help kill bacteria. NADPH oxidase is electrogenic,[26] moving electrons across the membrane, and proton channels open to allow proton flux to balance the electron movement electrically.[27]

Ligand-gated ion channels (LICs):

It also commonly referred as ionotropic receptors, are a group of transmembrane ion channel proteins which open to allow ions such as Na+, K+, Ca2+, and/or Cl− to pass through the membrane in response to the binding of a chemical messenger (i.e. a ligand), such as a neurotransmitter.[28]

When a pre-synaptic neuron is excited, it releases neurotransmitter from vesicles into the synaptic cleft. The neurotransmitter then binds to receptors located on the postsynaptic neuron. If these receptors are ligand-gated ion channels, a resulting conformational change opens the ion channels, which leads to a flow of ions across the cell membrane. This, in turn, results in either a depolarization, for an excitatory receptor response, or a hyperpolarization, for an inhibitory response. These proteins are typically composed of at least two different domains: a transmembrane domain which includes the ion pore, and an extracellular domain which includes the ligand binding location (an allosteric binding site).

This modularity has enabled a 'divide and conquer' approach to finding the structure of the proteins (crystallising each domain separately). The function of such receptors located at synapses is to convert the chemical signal of presynaptically released neurotransmitter directly and very quickly into a postsynaptic electrical signal. Many LICs are additionally modulated by allosteric ligands, by channel blockers, ions, or the membrane potential. LICs are classified into three superfamilies which lack evolutionary relationship: cys-loop receptors, ionotropic glutamate receptors and ATP-gated channels.

(d) CLASSIFICATION BY CELLULAR LOCALIZATION:

Ion channels are also classified according to their subcellular localization. The plasma membrane accounts for around 2% of the total membrane in the cell, whereas intracellular organelles contain 98% of the cell's membrane. The major intracellular compartments are endoplasmic reticulum, Golgi apparatus, and mitochondria. On the basis of localization, ion channels are classified as: The endoplasmic reticulum (ER) is a type of organelle in eukaryotic cells that forms an interconnected network of flattened, membrane-enclosed sacs or tube-like structures known as cisternae. The membranes of the ER are continuous with the outer nuclear membrane. The endoplasmic reticulum occurs in most types of eukaryotic cells, including Giardia [29] but is absent from red blood cells and spermatozoa. There are two types of endoplasmic reticulum: rough and smooth.

The outer (cytosolic) face of the rough endoplasmic reticulum is studded with ribosomes that are the sites of protein synthesis. The rough endoplasmic reticulum is especially prominent in cells such as hepatocytes. The smooth endoplasmic reticulum lacks ribosomes and functions in lipid manufacture and metabolism, the production of steroid hormones, and detoxification.The Golgi apparatus, also known as the Golgi complex, Golgi body, or simply the Golgi, is an organelle found in most eukaryotic cells. [27]

It was identified in 1897 by the Italian scientist Camillo Golgi and named after him in 1898. Part of the cellular endomembrane system, the Golgi apparatus packages proteins into membrane-bound vesicles inside the cell before the vesicles are sent to their destination. The Golgi apparatus resides at the intersection of the secretory, lysosomal, and endocytic pathways. It is of particular importance in processing proteins for secretion, containing a set of glycosylationenzymes that attach various sugar monomers to proteins as the proteins move through the apparatus. The mitochondrion (plurandria) is a double membrane-bound organelle found all eukaryotic organisms. Some cells in some multicellular organisms may however lack them (for example, mature mammalian red blood cells).

A number of unicellular organisms, such as microsporidia, parabasalids, and diplomonads, have also reduced or transformed their mitochondria into other structures.[1,2] To date, only one eukaryote, Monocercomonoides, is known to have completely lost its mitochondria The word mitochondrion comes from the Greek μίτος, mitos, "thread", and , chondrion, "granule"[31]or "grain-like". Mitochondria generate most of the cell's supply of adenosine triphosphate (ATP), used as a source of chemical energy.[32]

OTHER CLASSIFICATIONS:

There are other criteria for ion channel classification, including multiple pores and transient potentials. Almost all ion channels have a single pore. However, there are also those with two pores:

Two pore ion channels:

Two-pore channels (TPCs) are eukaryotic intracellular voltage-gated and ligand gated cations selective ion channels [33].With two known paralogs in the human genome and are found to be expressed in both plant vacuoles and animal acidic organelles. These organelles consist of endosomes and liposomes. [34]

TPCs are formed from two transmembrane non-equivalent tandem Shaker-like, pore-forming subunits, dimerized to form quasi-tetramers. TPCs regulate sodium and calcium ion conductance, intravasicular pH, and trafficking excitability. Activation of TPCs is induced by a decrease in transmembrane potential, or an increase in calcium concentrations in the cytosol.Inhibition may be caused by low pH of the lumen and low calcium concentration. Regulation by phosphorylation can open the pore in both plants and animals.The second messenger nicotinic acid adenine dinucleotide phosphate (NAADP) has been shown to mediate calcium release from these acidic organelles through TPCs. This two-member family is thought to form cation-selective ion channels. They appear to contain two KV-style six-transmembrane domains, suggesting that they form a dimer in the membrane. These channels are related to cation channels of sperm and, more distantly, TRP channels. [34]

(f) THERE ARE CHANNELS THAT ARE CLASSIFIED BY THE DURATION OF THE RESPONSE TO STIMULI:

Transient receptor potential channels:

Transient receptor potential channels (TRP channels) are a group of ion channels located mostly on the plasma membrane of numerous animal cell types. There are about 28 TRP channels that share some structural similarity to each other. These are grouped into two broad groups: Group 1 includes TRPC (“C" for canonical), TRPV ("V" for vanilloid), TRPM ("M" for melastatin), TRPN, and TRPA. In group 2, there are TRPP ("P" for polycystic) and TRPML ("ML" for mucolipin). Many of these channels mediate a variety of sensations like the sensations of pain, hotness, warmth or coldness, different kinds of tastes, pressure, and vision. In the body, some TRP channels are thought to behave like microscopic thermometers and used in animals to sense hot or cold.[36] Some TRP channels are activated by molecules found in spices like garlic (allicin), chilli pepper (capsaicin), wasabi (allyl isothiocyanate); others are activated by menthol, camphor, peppermint, and cooling agents; yet others are activated by molecules found in cannabis (i.e., THC, CBD and CBN) or stevia. Some act as sensors of osmotic pressure, volume, stretch, and vibration.

Figure-6: Thermal activation of transient receptor potential channel (Direct mode and indirect mode)

Ion channel blockers:

A variety of inorganic and organic molecules can modulate ion channel activity and conductance. Some commonly used blockers include [34,37]

(a) Tetrodotoxin used by puffer fish and some types of newts for defense. It blocks sodium channels.

(b) Saxitoxin is produced by a dinoflagellate also known as “red tide". It blocks voltage-dependent sodium channels.

(d) Lidocaine and Novocaine belong to class oflocal anaesthetics which block sodium ion channels.

(e) Dendrotoxin is produced by mamba snakes, and blocks potassium channels.

(f) Iberiotoxin is produced by the BUTHUS tumulus (Eastern Indian scorpion) and blocks potassium channels.

(g) Heteropodatoxin is produced by Heteropoda Venatoria (brown huntsman spider or laya) and blocks potassium channels.[36]

CONCLUSION:

Ion channels are made up of glycoprotein made by aggregation of subunits forming a variety of tube by which specific ions can permeate andthey capable to modify the membrane potential in the either intracellular to extracellular or extracellular to intracellular or side of the membrane those in turnregulating their opening and closing of the channel. These channels are located within the transmembrane of most of the cells and of many intracellular organelles. Most of the ion channels are specific in nature and to certain ions are permeates through it, where as some other channels may be permeable to the passage of more than one type of ion, typically giving out a common charge: positive (Cations) or negative (anions).They played a important role in excitation and inhibition of different types of cells depending upon types of ions permitted and permeated through the specific channels which causes the depolarization or hyper polarization etc of the cell.

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Received on 20.11.2017 Modified on 10.01.2018

Res. J. Pharmacology and Pharmacodynamics.2018; 10(1): 38-44.

DOI: 10.5958/2321-5836.2018.00007.1