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Membrane Protein Channels Potassium ions queuing up in the potassium channel Pumps: 1000 s-1 Channels: 1000000 s-1 Pumps & Channels • The lipid bilayer of biological membranes is intrinsically impermeable to ions and polar molecules. • Permeability is conferred by two classes of membrane proteins, pumps and channels. • Pumps use an energy source (ATP or light) to drive the thermodynamically uphill transport of ions or molecules. • Channels, in contrast, enable downhill or passive transport (facilitated diffusion). Propagation of nerve impulses We shall examine three channels important in the propagation of nerve impulses: the ligand gated channel (for which the acetylcholine receptor is the paradigm and which communicates the nerve impulse between certain neurons); and the voltage gated Na+ and K+ channels, which conduct the nerve impulse down the axon of a neuron. Nerve communication across synapses • Ligand gated channel • Acetylcholine is a cholinergic neurotransmitter • 50 nm synaptic cleft • Synaptic vesicles have 10000 acetylcholine molecules Nerve communication across synapses • Synchronous export of 300 vesicles in response to a nerve impulse. • Acetylcholine concentration increases from 10nM to 0.5mM in a ms. • The binding of acetylcholine to the postsynaptic membrane changes its ionic permeabilities. The conductance of Na+ and K+ increases in 0.1 ms, leading to a large inward current of Na+ and a smaller outward flux of K+. Nerve communication across synapses • The inward Na+ current depolarises the plasma membrane and triggers an action potential. Acetylcholine opens a single type of cation channel, which is almost equally permeable to Na+ and K+. • This change in permeability is mediated by the acetyl-choline receptor. Acetylcholine receptor 2a, b, g, d Pseudo five fold symmetry Acetyl choline receptor - a ligand gated ion channel Voltage gated channels (K+ & Na+ channels) • The nerve impulse is an electrical signal produced by the flow of ions across the plasma membrane of a neuron. • The interior of the neuron has a high concentration of K+ and a low concentration of Na+. • These gradients are produced by a Na+-K+ ATPase. Action potential – signals are send along neurons by transient depolarization & repolarization Depolarization beyond a threshold causes Na+ ions to flow in leading to further depolarisation & more Na+ influx K+ ions flow out restoring the membrane potential Causes –60 to + 30 mV in a ms There must be specific ion channels Potassium & Sodium Channels Hydrophobic except S4 – positively charged Protein purified on the basis that it could bind tetrodotoxin (from the puffer fish) binds Na+ channels with Ki ~ 1nM – lethal dose for adult 10ng. Structure of the potassium ion channel Potassium ion channel Path through the K+ channel Inside cell Selectivity filter Thr-Val-Gly-Tyr-Gly Selectivity of K+ channel • Ions with radius > 1.5Å are too big to fit through the channel of 3.0Å diameter • Na+ is not so well solvated by the protein Voltage gated requires substantial conformational change Model for activation - S1 to S4 form the voltage responsive paddles The channel can be inactivated by occlusion of the pore “Ball and chain model” Trypsin cleaved channel (cytoplasmic tail) does not inactivate. Neither does a mutant lacking 42 Nterminal residues Adding back the peptide 120 restores inactivation Na+ and K+ channels work together to give the action potential Na+ in first Then K+ out