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lecture5-ion channels-2012-with supplemental material.pdf

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BIOL 4510
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BIOL4510 / KINE 4510 Ion Channels 1 & 2 Peter Backx Ion channels are a superfamily of transmembrane proteins that selectively catalyze the flow (movement) of ions across the cell membrane. Ion channels are enzymes. Their properties include gating (allosteric regulation), selectivity and permeation. Gating refers to the process of channels opening and closing which essentially involves the allosteric regulation of the active site. The active site is the "pore" (i.e. the hole formed in the membrane) that allows for the passage of ions in a highly selective manner (i.e. ion channel discriminate between different types of ions and are therefore classified on the basis of the type of ion they pass through the membrane. Permeation is the rate at + which an ion can translocate through the channel. Channel are remarkably selective: K channels are 10000X more selective for K than Na ) but still allow over 10 ions to flow per second. Ions cannot diffuse across the lipid membrane due to the high energy barrier (~30 kT). Ion channels allow for the movement of ions across the membrane via a low energy water-filled conduction pathway. Because of ionic gradient across cell membranes, changes in ion channel activity lead to action potentials which are critical in a number of cellular functions: 1) cardiac, skeletal and smooth muscle contraction 2) cellular excitability 3) secretion of neurotransmitters and hormones 4) regulation of cell volume 5) maintaining ionic gradients across the membrane 6) touch (sensing pain, temperature), smell, vision, hearing, taste 7) cell growth and death 8) consciousness, thought, memories 1 Classification of Ion Channels: Ion channels are classified on the basis of: 1. Ionic selectivity 2. Functional properties a) voltage-gated channels b) ligand-gated channels c) mechanosensitive channels 3. Molecular properties For example, one of the key ion channels in the heart is the voltage-gated sodium channel. These channels are highly selective for Na + versus other ions (explained later), their activity is highly regulated by voltage (also explained later) and they have a rather complicated molecular structure being compromised of several proteins with well defined structures. Cardiac Action Potential The cardiac action potential is a composite of the integrative activity of numerous ion channels. It can be divided into 5 distinct phases: 1) phase 0 upstroke of the action potential initiated primarily by the activation of voltage-gated sodium channels (I )Na 2) phase 1 initial repolarization due to the opening of transient outward potassium channels (Ito1) 3) phase 2 plateau phase balance between depolarizing Ca 2+ currents through L- 2+ type (or dihydropyridine-sensitive) Ca channels (I Ca-L) and repolarizing potassium currents through a number of different voltage-gated potassium channels, ultrarapidly activating delayed potassium channel ( Kur) and rapidly-activating delayed rectifying potassium channels, (IKr 2 4) phase 3 repolarization due to the reduction in I Ca-L, and an increase in I , Kr slowly-activating delayed rectifying potassium (IKs, and the inwardly-rectifying potassium channel (I ) K1 5) phase 4 resting potential controlled primarily by IK1 however in other cells types the pacemaker current (I ) or f the acetylcholine-sensitive K + channel (I K-ACh) also contributes to the resting membrane potential Other ion channels, ion exchangers and ion pump can also modify the action potential waveform. The interactions between different ion channels (currents) during the cardiac action potential will be discussed below. 3
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