Ion Channels PDF

Ion Channels OUTLINE A Brief definition of Ion Channels Characters of ion channels Biological role of ion channels Types and Classification 2 ION CHANNELS??! Ion channels are membrane protein complexes, and they play an ess...

Ion Channels OUTLINE A Brief definition of Ion Channels Characters of ion channels Biological role of ion channels Types and Classification 2 ION CHANNELS??! Ion channels are membrane protein complexes, and they play an essential role in the diffusion of ions across cell membrane. Why do we need ion channels? Membranes are phospholipid bilayers, and they build a hydrophobic, low dielectric barrier to hydrophilic and charged molecules. Charged molecules or atoms can not penetrate this barrier. Ion channels provide a high conducting, hydrophilic pathway across the hydrophobic interior of the membrane. 3  The activity of many ion channels is regulated by protein phosphorylation and dephosphorylation 350px-Ion_channel Schematic diagram of an ion channel: 1 - channel domains (typically four per channel), 2 - outer vestibule, 3 – selectivity filter, 4 - diameter of selectivity filter, 5 – phosphorylation site, 6 – cell membrane. 4 Differences between ion channels and carrier proteins 1. Unlike carrier proteins, channel proteins form hydrophilic pores across membranes. 2. One class of channel proteins found in all animals, forms gap junctions between two adjacent cells; each plasma membrane contributes equally to the formation of the channel, which connects the cytoplasm of the two cells. 5 Characters of Ion Channels Selectivity: channel proteins in the plasma membrane of animal and plant cells connect the cytosol to the cell exterior and necessarily have narrow, highly selective pores. These proteins are concerned specifically with inorganic ion transport and so are referred to as ion channels. Transport efficiency: channels have an advantage over carriers in that more than 1 million ions can pass through one channel each second, which is a rate 1000 times greater than the fastest rate of transport mediated by any known carrier protein. 6  Structure of K+ Channel Multiple Functional Adaptations Selectivity Filter Characters of Ion Channels Passive transport: channels cannot be coupled to an energy source to carry out active transport, so the transport they mediate is always passive ("downhill"). The function of ion channels is to allow specific inorganic ions, mainly Na+, K+, Ca2+, or Cl-, to diffuse rapidly down their electrochemical gradients across the lipid bilayer. This does not mean that the transport through ion channels cannot be regulated. The ability to control ion fluxes in this way is essential for many cell functions. 8 Differences between ion channels from simple aqueous pores Ion selectivity: permitting some inorganic ions to pass but not others. This suggests that their pores must be narrow enough in places to force permeating ions into intimate contact with the walls of the channel so that only ions of appropriate size and charge can pass. Gating: Ion channels are not continuously open. Instead, they have "gates," which open briefly and then close again. In most cases the gates open in response to a specific stimulus. 9 Biological role of ion channels 1. Ion channels mediate most forms of electrical signaling in the nervous system: "voltage-activated" channels underlie the nerve impulse. "transmitter-activated" channels mediate conduction across the synapses. most of the offensive and defensive toxins that organisms have evolved for shutting down the nervous systems of predators and prey (e.g., the venoms produced by spiders, scorpions, snakes, fish, bees, sea snails and others) work by modulating ion channel conductance 10 Biological role of ion channels 2. Ion channels are responsible for the electrical excitability of muscle cells. Membrane potential: the voltage difference that is present across all plasma membranes. 3. 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. 4. In the search for new drugs, ion channels are a frequent target. 11  Specialized Functions of Ion Channels Mediate the generation, conduction and transmission of electrical signals in the nervous system Control the release of neurotransmitters and hormones Initiate muscle contraction Transfer small molecules between cells (gap junctions) Mediate fluid transport in secretory cells Control motility of growing and migrating cells Provide selective permeability properties important for various intracellular organelles  How ion channels work Gating: The conformational change between open, the conformation in which channel allow ions to pass, and closed, the conformation in which channel forbid ions to pass. Ion channels can be classified according to their gating mechanism. 13 Ion channel fluctuates between closed and open conformations. A transmembrane protein complex forms a hydrophilic pore across the lipid bilayer only when the gate is open. Polar amino acid side chains are thought to line the wall of the pore, while hydrophobic side chains interact with the lipid bilayer. The pore narrows to atomic dimensions in one region (the "ion- selective filter"), where the ion selectivity of the channel is largely determined. Voltage-gated ion channel in its closed, open, and inactivated states. The inactivated channel is still in its open state, but the ball domain blocks ion permeation. 14  Ion Channels Are Ion Selective and Fluctuate Between Open and Closed States The main types of stimuli that are known to cause ion channels to open are: 1. a change in the voltage across the membrane (voltage-gated channels), 2. a mechanical stress (mechanically gated channels), 3. the binding of a ligand (ligand-gated channels). The ligand can be either an extracellular mediator - specifically, a neurotransmitter (transmitter-gated channels) - or an intracellular mediator, such as an ion (ion-gated channels), or a nucleotide (nucleotide-gated channels) 15 Types Of Ion Channels (Gating Mechanisms) 16 Types Of Ion Channels Voltage-Gated: Open or close in response to change in charge across the plasma membrane. They are found in muscle or neuron cells. Ligand-Gated: Open or close in response to binding of small signaling molecule (ligand). Ligand can be intra cellular or extra cellular. They are found especially in synapses. Stretch-activated: They are mechanically gated channels, and opening of these channels creates nerve impulses. 18 Gated ion channels 19 Classification by Gating 1. Voltage-gated Voltage-gated ion channels open and close in response to membrane potential. 20 Classification by Gating 1. Voltage-gated Voltage-gated sodium channels: responsible for action potential creation and propagation. The pore-forming α subunits are very large (up to 4,000 amino acids) and consist of four homologous repeat domains (I-IV). The members of this family also co-assemble with auxiliary β subunits, 21 Classification by Gating 1. Voltage-gated Voltage-gated calcium channels: - play an important role in both linking muscle excitation with contraction as well as neuronal excitation with transmitter release. The α subunits have an overall structural resemblance to those of the sodium channels and are equally large. - Cation channels of sperm: This small family of channels, normally referred to as Catsper channels, is related to the two-pore channels and distantly related to TRP channels. 22 Classification by Gating 1. Voltage-gated Voltage-gated potassium channels (KV): These channels are known mainly for their role in repolarizing the cell membrane following action potentials. The α subunits have six transmembrane segments, homologous to a single domain of the sodium channels. Correspondingly, they assemble as tetramers to produce a functioning channel. 23 Classification by Gating 1. Voltage-gated Hyperpolarization-activated cyclic nucleotide-gated channels: The opening of these channels is due to hyperpolarization rather than the depolarization required for other cyclic nucleotide-gated channels. These channels are also sensitive to the cyclic nucleotides cAMP and cGMP, which alter the voltage sensitivity of the channel’s opening. These channels are permeable to the monovalent cations K+ and Na+. There are 4 members of this family, all of which form tetramers of six-transmembrane α subunits. As these channels open under hyperpolarizing conditions, they function as peacemaking channels in the heart, particularly the SA node. 24 Classification by Gating 1. Voltage-gated Voltage-gated proton channels: Voltage-gated proton channels opening with depolarization, but in a strongly pH-sensitive manner. 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. Another important function occurs in phagocytes (e.g. eosinophils, neutrophils, macrophages). 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, moving electrons across the membrane, and proton channels open to allow proton flux to balance the electron movement electrically. 26 Classification by Gating 2. Ligand-gated 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. Examples: the cation-permeable: "nicotinic" Acetylcholine receptor, ionotropic glutamate-gated receptors the anion-permeable: γ-aminobutyric acid-gated (GABA) receptor. Ion channels activated by second messengers may also be categorized in this group, although ligands and second messengers are otherwise distinguished from each other. 28 Classification by Gating 3. Other gating Other gating include activation/inactivation by e.g. second messengers from the inside of the cell membrane, rather as from outside, as in the case for ligands. Ions may count to such second messengers, and then causes direct activation, rather than indirect, as in the case were the electric potential of ions cause activation/inactivation of voltage-gated ion channels. 29 Classification by Gating 3. Other gating Some potassium channels Inward-rectifier potassium channels: These channels allow potassium to flow into the cell in an inwardly rectifying manner, i.e, potassium flows effectively into, but not out of, the cell. These channels are affected by intracellular ATP, PIP2, and G-protein βγ subunits. They are involved in important physiological processes such as the pacemaker activity in the heart, insulin release, and potassium uptake in glial cells. Calcium-activated potassium channels: This family of channels is activated by intracellular Ca2+ Two-pore-domain potassium channels: This family form what is known as leak channels. 30 Classification by Gating 3. Other gating Light-gated channels like channel rhodopsin (sensory photoreceptor) are directly opened by the action of light. Mechanosensitive ion channels are opening under the influence of stretch, pressure, shear, displacement. Cyclic nucleotide-gated channels: This family of channels is characterized by activation due to the binding of intracellular cAMP or cGMP, with specificity varying by member. These channels are primarily permeable to monovalent cations such as K+ and Na+. They are also permeable to Ca2+, though it acts to close them. 31 Classification by Ions Chloride channels Potassium channels Voltage-gated potassium channels Calcium-activated potassium channels Inward-rectifier potassium channels Two-pore-domain potassium channels Sodium channels Calcium channels Proton channels Voltage-gated proton channels General ion channels: These are relatively non-specific for ions and thus let many types of ions through the channel. Most Transient receptor potential channels 32 Other classifications There are other types of ion channel classifications that are based on less normal characteristics, e.g. multiple pores and transient potentials. Almost all ion channels have one single pore. However, there are also those with two: Two-pore channels: This small family of 2 members putatively forms cation-selective ion channels. They contain two KV-style six- transmembrane domains, suggesting they form a dimer in the membrane. These channels are related to catsper channels (cation channels of sperm) and, more distantly, TRP channels. 33 Other classifications There are channels that are classified by the duration of the response to stimuli: Transient receptor potential channels: This group of channels, normally referred to simply as TRP channels, is named after their role in Drosophila (fruit flies) phototransduction. This family is diverse in its method of activation. Some TRP channels seem to be constitutively open, while others are gated by voltage, intracellular Ca2+, pH, redox state, osmolarity, and mechanical stretch. These channels also vary according to the ion(s) they pass, some being selective for Ca2+ while others are less selective, acting as cation channels. 34 Any Questions?? 35 36