Enzymes and Ion Channels PDF
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This document is a set of lecture notes covering various topics in biology, focusing on enzymes, ion channels, and transporters. The lecture notes include diagrams and textual explanations of the different mechanisms.
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Enzymes are Highly Specific Protein Catalysts A Catalyst Increases the Rate of a Chemical Reaction does not alter Health and Science Academy - General Biology ...
Enzymes are Highly Specific Protein Catalysts A Catalyst Increases the Rate of a Chemical Reaction does not alter Health and Science Academy - General Biology Kinases are Proteins that Regulate the Activity of Other Proteins by Phosphorylation used up cAMP Activates Protein Kinase A (PKA) Regulation of a multitude of cellular events Acetylcholinesterase is the Enzyme Responsible for “Turning Off” the Neurotransmitter Signal turns off signal! cleaved Acetylcholinesterase Cleaves Acetylcholine to Yield Acetic Acid and Choline https://www.atsdr.cdc.gov/csem/csem.asp?csem=11&po=5 Ion Channels Voltage-gated – Sodium – Potassium – Calcium Ligand-gated (extracellular ligand) – Nicotinic acetylcholine receptor acetylcholine – TRPV1 capsaicin Ligand-gated (intracellular ligand) – CNG channel cAMP – TRPM5 Intracellular calcium Ion Channels Usually large multimeric integral membrane proteins Complex activation and regulation Multiple conductance states Filter selectivity can be regulated Very rapid responses – < milliseconds Voltage-gated Potassium Channel Distribution of Ions Inside and Outside of a Neuron * ☒IS Changes in Conformation Cause Changes in Ion Channel Conductance Conductance = rate of ion flow Flow of Ions Open Open Closed Open State State State State 2 3 1 Increasing Conductance Ion Channel Agonists Can Stabilize an Open State and Increase its Frequency “Patch Clamp” can measure the conductance of a single ion channel Basal Activity millivolts Agonist ✗ XX XX xxx ↑ Frequency Voltage-gated Ion Channels Change Conformation in Response to Changes in Membrane Potential Closed and Open Conformations The Nicotinic Acetylcholine Receptor is a Ligand-gated Cation Channel Acetylcholine Nicotinic Receptors are Expressed on the Postsynaptic Side of the Neuromuscular Junction https://thebrain.mcgill.ca/flash/d/d_06/d_06_m/d_06_m_mou/d_06_m_mou.html Transporters are Integral Membrane Proteins that Move Neurotransmitters and Hormones Across Membrane Barriers Transporters are highly selective Daniel P. Bermingham, and Randy D. Blakely Pharmacol Rev 2016;68:888-953 Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics Role of Transporters in Drug Response Large integral membrane proteins Transport substances in or out of cells – normal metabolism – protection from toxins Can affect the A-D-M-E of drugs Can decrease concentration of drugs if efflux transporter – P-gp – p-glycoprotein Active Transport Primary – Requires energy, usually by ATPase activity Secondary – Couples indirectly to primary – Symporters and antiporters Facilitated Diffusion Passive diffusion – Does not require energy – Driven by gradients Ligand binding site – Principles of receptor occupancy apply – Saturable Major Transporters Families ABC – ATP Binding Cassette – Primary active transport – Requires hydrolysis of ATP – P-gp (P-glycoprotein, or mdr1) – “vectorial” = uni-directional (efflux) SLC – Solute Carrier – Facilitated or secondary active transport – Neurotransmitter transporters – SERT, NET, DAT – Bi-directional (influx and efflux) P-gp Mechanism of Action Inward facing conformation A. Substrate (magenta) partitions into the bilayer from outside the cell to the inner leaflet and enters the internal drug-binding pocket through an open portal. The residues in the drug-binding pocket (cyan spheres) interact with inhibitors and substrates in the inward-facing conformation. B. Adenosine triphosphate (ATP) (yellow) binds to the nucleotide-binding domains, causing a large conformational change presenting the substrate and drug-binding site(s) to the outer leaflet/extracellular space. Jeffrey D. Wessler et al. J Am Coll Cardiol 2013; 61:2495-2502. SLC Transporters Operate both by Facilitated Diffusion and Secondary Active Transport ↓ Uniporters transport one substrate down its concentration gradient Symporters move both substrates in the same direction Antiporters move one substrate in by moving another out Lekholm, Emilia. “Solute Carriers in Metabolism : Regulation of known and putative solute carriers in the central nervous system.” (2017). Do all drugs require “targets” to be pharmacologically active? Antacids Bulk Laxatives Chelating Agents Volatile gases - Anesthesia