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Channels
- 1. ION CHANNELS Presented BY: KAVYA. J II M.Sc. Biochemistry
- 2. Introduction Biological membranes - highly selective, permeable barriers that surround distinct cellular compartments. The plasma membrane separates the inside of the cell from the extracellular environment, and within eukaryotic cells, additional membranes separate specialized compartments from the cytosol. Cellular compartments differ markedly in the composition of their membranes and internal environment. Throughout evolution, cells have developed sophisticated mechanisms to precisely maintain and regulate the composition of each compartment.
- 3. Continued The maintenance of solute concentrations across membranes is a prerequisite for cellular homeostasis. Homeostasis is the ability of cells to maintain a relatively constant internal environment for metabolic processes that are vital for survival. The homeostatic regulation of cytosolic ion concentrations also determines the relative osmotic pressures on each side of the cell membrane and thereby regulates the cell volume.
- 4. Mediated and non-mediated transport Mediated transport Through the action of various carriers Non-mediated transport Occurs through simple diffusion; chemical potential gradient is the driving force Transport processes
- 6. Transport across membranes Because the interior of the lipid bilayer is hydrophobic, it is essentially impermeable to polar, hydrophilic and large biological molecules. How do inorganic ions and charged and water-soluble molecules move into and out of cells and across intracellular membranes in a selective manner? Transport proteins reside in the plasma membrane and in membranes of intracellular organelles such as endoplasmic reticulum(ER), golgi apparatus, endosomes, lysosomes, and mitochondria transport proteins are integral transmembrane proteins Each type of membrane has distinct complement of transport proteins, as do different cell types. There are two main classes of transport proteins, channel proteins and carrier proteins
- 7. Transport channels Channels and Carriers are the main types of membrane transport proteins Confer permeability to the membrane Allosteric proteins Some transport proteins are present in the plasma membrane, whereas others are present in the membranes of intracellular organelles To maintain the composition of the cell and its intracellular compartments, it is important that transport are selective for a particular solute species over other.
- 9. Channels vs carriers Membrane transport proteins can be classified into two groups, channels and carriers, depending on the mode of transport. Channels, composed of one or more subunits, contain a pore region through which solute pass at high flux rates when the channel is open(acts like a tunnel) In contrast, carrier proteins bind solutes on one side of the membrane, undergo an allosteric(conformational) change, and release the solutes on the other side of the membrane(acts like a gate/door)
- 10. Properties of channels Constructed by the association of multiple homologous subunits or domains . Most channels are formed from four, five, six subunits The pore lies along the symmetry axis of the channel The pore is lined by α helices or β strands. Side chains emerging from these structural elements establish the selectivity of the channel. The acetylcholine receptor channel, for example, is selective for cations because its pore contains negatively charged rings. The degree of selectivity also depends on the diameter of the narrowest part of the pore. Channels formed from four subunit (the Na and the K channel) have the smallest pores(diameter 5Å and 3Å respectively) and are the most selective Channels are allosteric proteins that are gated by membrane potential , allosteric effectors, or covalent modification.
- 11. Transport channels: mode of operation Ungated channels A few types of channels are ungated, meaning they are open all the time. For instance, some K+ and some Cl– channels are ungated. By contrast, Ca2+ and Na+ ion channels are never ungated. Voltage gated channel This require a trigger, such as a change in membrane potential to unlock or lock the pore opening Voltage-gated ion channels are key in the generation of electrical signals in nerve, muscle, and cardiac cells.
- 12. Continued.. Ligand-gated channel Many ion channels open or close in response to binding a small signaling molecule or “ligand”. Some ion channels are gated by extracellular ligands; some by intracellular ligands. In both cases, the ligand is not the substance that is transported when the channel opens. Many neurotransmitter receptors are ligand gated channels. An example is the nicotinic acetylcholine receptor. This is the receptor that is found at the neuromuscular junction on skeletal muscle cells, and also at synapses in autonomic ganglia. Stress-gated channel This require a mechanical force applied to the channel for opening. Mechanically-gated channels are found in skin and also in the specialized sensory cells of the auditory and vestibular system.
- 14. Types of transport channels 1.Ion channels 2.Aquaporins
- 15. Ion channels Ion channels are pore-forming membrane proteins Located within the plasma membrane of nearly all cells and many intracellular organelles They are often described as narrow, water- filled tunnels that allow only ions of certain size and/or charge to pass through. This characteristic is called selective permeability
- 17. Functions Maintain cell resting potential: K and Cl channels Conduction of electrical signals: Na and K channels of nerve axon Synaptic transmission at nerve terminals Intracellular transfer of ions, metabolites Cell volume regulation: Cl channels Excitation-contraction coupling: Ca channels of skeletal and heart muscle
- 18. Voltage gated channels Voltage-gated ion channels - class of transmembrane proteins - 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 coordinated 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.
- 20. mechanism Crystallographic structural studies of a potassium channel have shown that, when a potential difference is introduced over the membrane, the associated electric field induces a conformational change in the potassium channel The conformational change distorts the shape of the channel proteins sufficiently such that the cavity, or channel, opens to allow influx or efflux to occur across the membrane This movement of ions down their concentration gradients subsequently generates an electric current sufficient to depolarize the cell membrane.
- 21. Types of voltage gated ion channels 1. Voltage gated sodium channels 2. Voltage gated potassium channels 3. Voltage gated calcium channels 4. Voltage gated chloride channels
- 23. Voltage gated sodium channels Analysis of the sodium channel function occurred in 1960’s, and in 1980, the voltage gated sodium channel was discovered essential in the nervous system and for the generation of action potentials in excitable cells, including nerve, muscle and neuroendocrine cell types Low levels in non-excitable cells- physiological role unclear structure is similar to that of most other voltage gated ion channels; subunits arranged in such a way so that a central pore is formed the first voltage gated ion channel to be cloned and sequenced Belongs to the superfamily of ion channels(first to be discovered)
- 24. Structure of voltage gated sodium channel consist of a highly processed α subunit, which is approximately 260 kDa, associated with auxiliary β subunits of 33-39 kDa [5]. Sodium channels in the adult central nervous system (CNS) and heart contain a mixture of β1 - β4 subunits, while sodium channels in adult skeletal muscle have only the β1 subunit. The pore-forming α subunit is sufficient for functional expression, but the kinetics and voltage-dependence of channel gating are modified by the β subunits and these auxiliary subunits are involved in channel localization and interaction with cell adhesion molecules, extracellular matrix and intracellular cytoskeleton. The α subunits are organized in four homologous domains (I–IV), which each contain six transmembrane alpha helices (S1–S6) and an additional pore loop located between the S5 and S6 segments The pore loops line the outer entry to the pore while the S5 and S6 segments line the inner cavity and form activation gate at the inner exit from the pore. The S4 segments in each domain contain positively charged amino acid residues (usually arginine) at every third position. These residues serve as gating charges and move across the membrane in order to initiate channel activation in response to depolarization. The short intracellular loop connecting homologous domains III and IV serves as the inactivation gate, folding into the channel structure and blocking the pore from the inside during sustained depolarization of the membrane.
- 26. Voltage gated potassium channels Potassium channels are membrane proteins that allow rapid and selective flow of 𝐾+ ions across the cell membrane, and thus generate electric signals in cells Voltage-gated 𝐾+ channels- present in all animal cells Kv channels are one of the key components in generation and propagation of electrical impulses in nervous system The opening and closing of the channel depends upon changes in the transmembrane potential Upon changes in transmembrane potential, these channels open and allow passive flow of 𝐾+ ions from the cell to restore the membrane potential
- 28. Voltage gated calcium channels Voltage gated calcium(𝐶𝑎2+ ) channels are key transducers of membrane potential changes that initiate many physiological events There are ten members of the voltage gated 𝐶𝑎2+ family in mammals They serve distinct roles in cellular signal transduction The 𝐶𝑎𝑣1 subfamily initiates contraction, secretion, regulation of gene expression, integration of synaptic input in neurons, and synaptic transmission at ribbon synapses in specialized sensory cells The subfamily 𝐶𝑎𝑣 2 is primarily responsible for initiation of synaptic transmission at fast synapses The subfamily 𝐶𝑎𝑣3 is important for repetitive firing of action potential in rhythmically firing cells such as cardiac myocytes and thalamic neurons
- 31. Voltage gated CHLORIDE CHANNELS Unlike 𝐶𝑎2+ , 𝐶𝑙− does not seem to play a role as intracellular messenger In mammals, the gene family of chloride channels has nine members that may function in the plasma membrane or in intracellular compartments CLC proteins were thought to have probably 10 or 12 transmembrane domains, 2 nucleotide binding folds(NBFs) The cellular functions of plasma membrane 𝐶𝑙− channels may be grouped Cell volume regulation Ionic homeostasis Transepithelial transport Regulation of electrical excitability
- 32. Continued.. Ionic homeostasis and cell volume regulation Cl channels play a crucial role in controlling the ionic composition of cytoplasm and the volumes of cells This function is performed in a closed interplay with various ion transporters, including pumps, co transporters and other ion channels
- 33. THANK YOU
Editor's Notes
- Crystallographic structural studies of a potassium channel have shown that, when a potential difference is introduced over the membrane, the associated electric field induces a conformational change in the potassium channel. The conformational change distorts the shape of the channel proteins sufficiently such that the cavity, or channel, opens to allow influx or efflux to occur across the membrane. This movement of ions down their concentration gradients subsequently generates an electric current sufficient to depolarize the cell membrane. 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.[6] 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.[3] 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 move toward the exoplasmic surface of the membrane. It is thought that the first 4 arginines account 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 that opens the channel.[4] 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.[7] Movement of the voltage-sensor triggers a conformational change of the gate of the conducting pathway, controlling the flow of ions through the channel.[3] 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 shape, which appears to be a conserved 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 phosphatases in various species.[8] 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.[9] 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.[10] 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.[11] 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,[12] the S6 segment breaks into two segments allowing of passing of ions through the channel,[13] or the S6 channel serving as the gate itself.[14] The mechanism by which the movement of the S4 segment affects that of S6 is still unknown, however it is theorized that there is a S4-S5 linker whose movement allows the opening of S6.[3] 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.[15] 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.[16] Fast inactivation is directly linked to the activation caused by intramembrane movements of the S4 segments,[17] though the mechanism linking movement of S4 and the engagement of the inactivation gate is unknown.