Ion Channels Lecture PDF

PUBLIC / CYHOEDDUS Ion Channels  PUBLIC / CYHOEDDUS Aims and Objectives Define types of ion channels found in vertebrates Understand molecular structure and function of ve...

PUBLIC / CYHOEDDUS Ion Channels  PUBLIC / CYHOEDDUS Aims and Objectives Define types of ion channels found in vertebrates Understand molecular structure and function of vertebrate voltage gated Na+ channel Understand molecular structure and function of vertebrate voltage gated Ca2+ channel Define key Ca2+ channel types and their locations  PUBLIC / Why Does It Exist? CYHOEDDUS Small buildup of negative ions in the cytosol along the inside of the membrane, and an equal buildup of positive ions in the extracellular fluid along the outside surface of the membrane  PUBLIC / Why Does It Exist? CYHOEDDUS This separation of charge is a form of potential energy, measured in mV The greater the difference in charge across the membrane, the larger the potential  PUBLIC / What’s the Evidence? CYHOEDDUS Hodgkin and Huxley (1952) https://youtu.be/k48jXzFGMc8 The tip of a recording microelectrode is inserted inside the cell, and a reference electrode is placed outside the cell in the extracellular fluid. The recording microelectrode and the reference electrode are connected to an instrument known as a voltmeter, which detects the electrical difference (voltage) across the plasma membrane  PUBLIC / Why the unequal distribution of ions in CYHOEDDUS the ECF and cytosol?  PUBLIC / CYHOEDDUS Contribution of the ECF Composition ECF is rich in Na+ and Cl-  PUBLIC / CYHOEDDUS Contribution of the Cytosol Composition ECF is rich in Na+ and Cl-. In cytosol, the main cation is K+ and the two dominant anions are phosphates attached to molecules, such as ATP and amino acids in proteins  PUBLIC / CYHOEDDUS Contribution of Leakage Channels The plasma membrane typically has more K+ leakage channels than Na+ channels Thus, the number of K+ that diffuse down their gradient out of the cell is greater than the number of sodium ions that diffuse down their gradient into the cell  PUBLIC / CYHOEDDUS Inability of most anions to leave the cell Most anions inside the cell are not free to leave They cannot follow the K+ out of the cell because they are attached to non-diffusible molecules such as ATP and large proteins  PUBLIC / CYHOEDDUS Contribution of the Na+/K+ ATPases The Na+/K+ ATPase pumps maintain the resting potential by pumping out Na+ as fast as it leaks in At the same time, they bring in K+, which leak back out of the cell down their gradient They expel 3 Na+ per K+ imported  PUBLIC / CYHOEDDUS Types of Ion Channel All allow passage of ions once opened Leak channels Randomly open and close; higher number of K+ leak channels than Na+ Found in nearly all cells, all along neurons Ligand-gated Opened by binding of a chemical stimulus e.g., hormones, neurotransmitters, ions Found at dendrites and cell bodies Mechanically gated Open in response to touch, vibration, stretch e.g., sound waves Found in receptors e.g., auditory, proprioceptors, touch, pressure receptors Voltage-gated Open in response to change in membrane potential (voltage) Propagate action potentials in all neuron axons  PUBLIC / Neuronal Ion Channels CYHOEDDUS Dendrites Synaptic bulbs Axon Principles of Human Anatomy and Physiology, 11e  Voltage Gated Sodium PUBLIC / CYHOEDDUS Channels α Beneski and Catterall 1980 “Well-designed” electrical machine for signalling capable of opening and closing within 0.001s and is composed of three subunits α: 260kDa, forms the pore β: much smaller ~ 30kDa regulate function and location within cell Voltage Gated Sodium PUBLIC / CYHOEDDUS Channels Sodium Channel Domains and PUBLIC / CYHOEDDUS Functions  Sodium Channel Domains and PUBLIC / CYHOEDDUS Functions Protein chain = 2000 amino acids which has 24 transmembrane segments  Sodium Channel Domains and PUBLIC / CYHOEDDUS Functions Protein chain = 2000 amino acids which has 24 transmembrane segments Organised into 4 domains, each of which has 4 segments involved in voltage sensing (S1-S4) and 2 further domains (S5 and S6) which  Sodium Channel Domains and PUBLIC / CYHOEDDUS Functions Protein chain = 2000 amino acids which has 24 transmembrane segments Organised into 4 domains, each of which has 4 segments involved in voltage sensing (S1-S4) and 2 further domains (S5 and S6) which  Molecular Mechanism of Fast PUBLIC / CYHOEDDUS Inactivation When the channel opens, the inactivation gate moves to its open position and then closes binds, and blocks sodium movement Inactivation gate has amino acid residues these are the latch that holds the inactivation gate closed  PUBLIC / Calcium Channels CYHOEDDUS α1 subunit forms the pore α2, β, γ, and δ subunits are auxiliary subunits not directly involved in voltage gating, or Ca2+ conduction Are involved in channel regulation and its cell biology https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4037393/  PUBLIC / Ca2+ Signals Initiate Many CYHOEDDUS Physiological Processes Activation of Ca2+ channels by electrical signal initiates cellular events Synaptic Transmission Secretion Muscular Contraction Enzymatic Regulation Important to note: Ca2+ channels must select for Ca2+ in the face of prevailing prevalence of Na+ I.e., [140 nM Na+] vs. [2 nM Ca2+]  PUBLIC / Structure of Calcium Channels CYHOEDDUS Large protein with four repeated domains Six transmembrane segments in each domain and most importantly… VERY large intracellular loops inside the protein Signalling platform for intracellular proteins to carry out calcium signalling or regulate the calcium channel  PUBLIC / Example - Calmodulin CYHOEDDUS  PUBLIC / Example - Calmodulin CYHOEDDUS RESTING Local Global Ca2+ Ca2+ Ca2+ INCREAS INCREAS E E  PUBLIC / Types of Calcium Channels CYHOEDDUS L Type – “Long Lasting” currents, high activation threshold, slow inactivation rate Found in Cardiac Muscle T-Type – “Transient” currents, low activation threshold, fast inactivation rate Found in SA node, endocrine cells some arteries