Ion channels

Ion channels

1. ION CHANNELS: A cell membrane channel that is selectively permeable to certain ions. A protein that acts as a pore in a cell membrane and permits the selective passage of ions (such as potassium ions, sodium ions, and calcium ions ) and by means of electrical current the selective ions passes in and out of the cell. Ions channels highly selective in the type of ions transported.

2. Introduction of Ion Channels: Ion channels are pore-forming membrane proteins whose functions is 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 membranes, and regulating cel l volume . Ion channels are located within the membrane of all excitable cells, and of many intracellular organelles. They are often described as narrow, water-filled tunnels that allow only ions of a certain size and charge to pass through. This characteristic is called selective permeability. 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. Discovery of Ion Channels: Fundamental properties of currents mediated by ion channels were analyzed by the British biophysicists Alan Hodgkin and Andrew Huxley in 1952 on their work on Action Potential. The existence of ion channels was confirmed in the 1970s by Bernard Katz and Ricardo Miledi by the invention of an electrical recording technique known as the "patch clamp“ by Erwin Neher and Bert Sakmann, the technique's inventors, who won a Nobel Prize for it. The Nobel Prize in Chemistry for 2003 was awarded to Roderick MacKinnon for his studies on the physio-chemical properties of ion channel structure and function, including x-ray crystallographic structure studies. Since the discovery of Ion Channels, the etiology of many diseases has been traced back to channelopathies. Many toxins produced by snake, fish, spider and other insects paralyze the Ion channels. Ion channels are recent target site for pharmaceutical biosynthesis of new drugs.

4. Basic Features of Ion Channel: There are two distinctive features of ion channels that differentiate them from other types of ion transporter proteins : The rate of ion transport through the channel is very high (often 10 6 ions per second or greater). Ions pass through channels down their electrochemical gradient, which is a function of ion concentration and membrane potential, "downhill", without the input (or help) of metabolic energy (e.g. ATP, co-transport mechanisms, or active transport mechanisms ) involves passive mechanism. Ion Channels allow only ions of a certain size and charge to pass through, this characteristic is called selective permeability .

5. Biological roles plays by Ion Channels: Conductance of nerve impulse, generation of action potential and synaptic transmission. Cardiac, skeletal, and smooth muscle contraction. Epithelial transport of nutrients and ions. T-cell activation (immune regulation). Pancreatic beta-cell insulin release.

6. Biological roles plays by Ion Channels:

7. Types of Ion Channels: There are different types of Ion channels so these are classified into four main categories which are further sub classified into different subclasses. Classification of Ion Channels Three main types of Ion Channels on the basis of: Nature of their gating. T ypes of ions passing through those gates. L ocalization of proteins in the cell. Other classification. Among these four classification our interest of study are these three main classification which have further more types. Other classification means which is on many other basis such as classification on the basis of number of gates and many others but that is not of our interest. Our main focus is three main classification of Ion channels and most important is first one classification named as classification on the basis of gating so, we study further types of first classification in detail.

8. Classification of Ion Channels: 1-Classification by the n ature of gating. 2- Classification by the t ypes of ions passing through those gates. 3- Classification by the l ocalization of proteins in the cell. 4- Other Classification of Ion Channels. 1.1 Voltage gated Ion Channel. 1.2 Ligand gated Ion Channel. 1.3 Other gated Ion Channel. 2.1 Chloride C hannel. 2.2 Potassium Channel. 2.3 Sodium Channel. 2.4 Calcium Channel. 2.5 Proton Channel. 3.1 Plasma Membrane Channel. 3.2 Intracellular Channel. This type of classification contain many types means classification on the basis of number of gates and many others.

9. Sub-Classification of Ion Channels: 1-Classification on the basis of gating: Cys -loop receptor. Inotropic glutamate receptor and many others. Light gated Ion Channels. Indirect Signaling and many others. 1.1 - Voltage Gated Ion Channel: 1.2 – Ligand Gated Ion Channel: 1.3 – Other gated Ion Channels: Voltage gated Sodium Ion Channels. Voltage gated Potassium Ion Channels. Voltage gated Calcium Ion Channels. Voltage gated Chloride Ion Channels and many others.

10. 1-Classification on the basis of gating. Ion channels may be classified by gating means what opens and closes the channels . Types: 1.1 - Voltage Gated Ion Channel: voltage-gated ion channels open or close depending on the voltage gradient across the plasma membrane. 1.2 – Ligand Gated Ion Channel: ligand-gated ion channels open or close depending on binding of ligands to the channel (to the extracellular domain of membrane protein). 1.3 – Other gated Ion Channels: These channels open and close in response to light and second messenger. For example, Light gated Ion Channels, Indirect Signaling and many more.

11. 1.1 - Voltage Gated Ion Channel: Voltage-gated ion channels open and close in response to membrane potential. Voltage Sensitive. Conformational change in response to potential gradient. Generally Ion specific. Important for Excitable cells like neurons. Role in the regulation of depolarization and polarization of neural membrane during an action potential. Distributed along axon and soma of neuron.

12. Structure and function of Voltage Gated Ion Channel: Several subunit with central pore . Ion specific but ion with similar charge and size can enter. Functionally governed by three main parts the voltage sensor, the pore and the gate. Na, K and Ca channels have transmembrane alpha subunits surrounding the pore. Six subunits: S1 – S6. S1-S4 have Voltage sensing region. S5- S6 have Gate and pore. Regulatory beta subunits.

13. STRUCTURE:

14. Mechanism of Action:

15. Mechanism of Action: Voltage gated Potassium ion channels: When a potential difference is introduced over membrane, the associated electric field induces a conformational change in the potassium channel. The conformational distorts the shape of channel protein sufficiently such that the cavity or channel, opens to allow influx or efflux to occur across the membrane. K ions move out of cell.

16. 1.1 - Voltage Gated Ion Channel: Types of Voltage gated Ion channel: Voltage-gated sodium channels : This family contains at least 9 members and is largely responsible for action potential creation and propagation (for membrane depolarization). The pore-forming α subunits are very large (up to 4,000 amino acids) and consist of four homologous repeat domains (I-IV) each comprising six transmembrane segments (S1-S6) for a total of 24 transmembrane segments. Voltage-gated calcium channels : This family contains 10 members. They regulate intracellular Ca2+ concentrations, and thus are responsible for a wide range of biochemical processes within cells. One of the most important processes regulated by these channels is the release of neurotransmitters at synapses.These channels play an important role in both linking muscle excitation with contraction as well as neuronal excitation with transmitter release. Voltage-gated potassium channels : This family contains almost 40 members, which are further divided into 12 subfamilies. These channels are known mainly for their role in repolarizing the cell membrane after action imperative in generating resting membrane potential.

17. Channel Structure The aplha subunits have six transmembrane segments, with a central pore.Ion specific. Functionally has three main parts i.e voltage senser, pore and gate.

18. 1.2 – Ligand Gated Ion Channel: This group of channels open in response to specific ligand molecules binding to the extracellular domain of the receptor protein. Ligand binding causes a conformational change in the structure of the channel protein that ultimately leads to the opening of the channel gate and subsequent ion flux across the plasma membrane.

19. Ligand Gated Ion Channel: Three super families: Cys-loop receptor. Ionotropic glutamate receptor. ATP gated channels. 1- Cys-loop Receptor: The name of the family refers to a characteristic loop formed by between two cysteine (Cys) residues, which form a disulfide bond near the N-terminal extracellular domain. Activated by specific neurotransmitter such as Acetyl choline, serotonin, glycine, glutamate, GABA means gamma- amino butyric acid in vertebrates. These receptors are composed of five protein subunits which form a pentameric arrangement around a central pore .

20. Structure of Cys- Receptor:

21. 2- Ionotropic glutamate receptor They are activated by the neurotransmitter glutamate and mediate most fast excitatory transmission in the CNS. Glutamate binds with N terminal. Consists of a tetramer. Each subunit consists of extracellular amino terminal domain (ATD, which is involved in tetramer assembly), an extracellular ligand binding domain(LBD, which binds glutamate), and a transmembrane domain (TMD, which forms the ion channel). 3- ATP Gated Channels : They are preferably permeable to Na+, K+ and Ca2+ and are activated by ATP. These receptors are widely expressed in many tissues and are shown to play key roles in various physiological processes, such as nerve transmission, pain sensation, and various inflammatory responses

22. Mechanism of receptor:

23. 2- Classification on the basis of types of ions passing through those gates. Chloride Channels : This superfamily of channels consists of approximately 13 members. These channels are non-selective for small anions; however chloride is the most abundant anion, and hence they are known as chloride channels. Potassium C hannels: Potassium channels are activated when intracellular ATP levels decrease, and are an important link between the cellular excitability and the metabolic status of the cell. Sodium C hannels: S odium channels are integral membrane proteins that form ion channels, conducting sodium ions (Na+) through a cell's plasma membran e. Calcium Channels : Calcium channels are membrane-spanning proteins that regulate the intracellular concentration of calcium ions (Ca2+). Proton Channels : Proton conductance

24. 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: Types: Plasma membrane channels : Examples: Voltage-gated potassium channels (Kv), Sodium channels (Nav), Calcium channels (Cav) and Chloride channels (ClC) Intracellular channels : which are further classified into different organelles. Endoplasmic reticulum channels: RyR, SERCA, ORAi Mitochondrial channels: mPTP, KATP, BK, IK, CLIC5, Kv7.4 at the inner membrane and VDAC and CLIC4 as outer membrane channels. 3- Classification on the basis of localization of proteins in the cell:

25. Pharmacology: Ion channel blockers: A variety of ion channel blockers (inorganic and organic molecules) block ion channels. Some commonly used blockers include: Tetrodotoxin (TTX), used by puffer fish and some types of newts for defense. It blocks sodium channels. Saxitoxin is produced by a dinoflagellate also known as "red tide". It blocks voltage-dependent sodium channels. Ion channel activator: Several compounds are known to promote the opening or activation of specific ion channels. These are classified by the channel on which they act: Calcium channel openers, such as Bay K8644. Chloride channel openers, such as phenanthroline.

26. Diseases: (Channelopathies) Channelopathies are diseases caused by disturbed function of ion channel subunits or the proteins that regulate them. These diseases may be either congenital (often resulting from a mutation or mutations in the encoding genes) or acquired (often resulting from autoimmune attack on an ion channel) Some channelopathies are shown as: Shaker gene mutations cause a defect in the voltage gated ion channels, slowing down the repolarization of the cell. Equine hyperkalaemic periodic paralysis as well as human hyperkalaemic periodic paralysis (HyperPP) are caused by a defect in voltage-dependent sodium channels. Paramyotonia congenita (PC) and potassium-aggravated myotonias (PAM ).

27. Channelopathy example PMC ( Paramyotonia congenita ):

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