Ion Channels and Drug Targets 2024 PDF

Ion channels as drug targets Alberto Capurro Neuroscience, Surgery and Trauma The Na+-K+ pump  Membrane potential - Every cell has a resting potential maintained by the Na+-K+ pump. - Only excitable cells (e.g., neurons, muscular cells) can also...

Ion channels as drug targets Alberto Capurro Neuroscience, Surgery and Trauma The Na+-K+ pump  Membrane potential - Every cell has a resting potential maintained by the Na+-K+ pump. - Only excitable cells (e.g., neurons, muscular cells) can also produce action potentials.  Ca++ ATPase pump Cl-/K+ co-transporter Cl- K+ Uses ATP to pump Ca++ out of the cytosol Uses K+ gradient created by the Na+/K+ ATPase to pump Cl- to the extracellular https://www.mpinat.mpg.de/652929/pr_1819  inactivation Dales Purves Neuroscience https://www.pinterest.co.uk/pin/6192518225178682/ Opening, inactivation and closure of Na+ and K+ channels during an action potential. Synaptic potentials Ligand gated receptors Glutamate receptors: NMDA, Insulin and growth AMPA, and kainate factor receptors IP₃ receptor and β-Adrenergic receptors steroid hormones receptors Na blockers: TTX -TTX -Saxitoxin -µ-conotoxins Na inactivation blockers: Alpha-conotoxins Batracotoxin K blockers: Dendritoxin Apamin  inactivation https://www.pinterest.co.uk/pin/6192518225178682/ Dales Purves Neuroscience Opening, inactivation and closure of Na+ and K+ channels during an action potential.  Cardiac action-potential https://www.sciencedirect.com/topics/medicine-and-dentistry/cardiac-action-potential Antiarrhythmic drugs These drugs regulate heart rhythms that are too fast by blocking cardiac ionic channels. They can be classified into different classes, including: Class I: Sodium channel blockers that can prolong or shorten the action potential Class II: Beta-adrenoceptor antagonists that slow sinus rhythm and atrioventricular conduction Class III: Potassium channel blockers that prolong the action potential Class IV: Calcium channel blockers that mainly slow atrioventricular conduction  Anti-epileptic drugs sites of action in ionic channels https://www.studocu.com/in/document/maulana-abul-kalam-azad-university-of- technology/medicinal-chemistry-i/mechanism-of-action-of-anticonvulsant-drugs/39564548 Examples of channels neurotransmitter > Benzodiazepines increase the frequency of the chloride channel opening, while barbiturates increase the duration of chloride channel opening. > Alcohol binds to allosteric sites on GABA-A receptors. In allosteric interactions, a ligand's binding to a receptor site changes how another ligand binds to a different site on the same receptor. Alcohol binding facilitates GABA binding. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC165791/ GABA post synaptic potential GABA post synaptic current Different types of GABA receptors  Serotonergic 5HT1 receptors https://www.semanticscholar.org/paper/Serotonin-receptors-in-depression%3A-from-A-to-B-Nautiyal-Hen/43903884a4c18fbebbff43083a3b2dd21daac03c Autoreceptors vs Heteroreceptors A presynaptic 5HT1A model of inhibitory autoreceptor down-regulation in response to ADT. (a) Untreated neuron has normal firing (spikes), transports 5-HT normally (circular arrows), with baseline effects at the post-synaptic receptor. (b) With acute ADT, the 5-HT transporter reuptake is inhibited, increasing extracellular concentrations of 5-HT (circles). The increased extracellular concentrations of 5-HT stimulate 5-HT1A autoreceptors to inhibit 5-HT neuron firing (single spike). (c) Chronic occupancy of the 5-HT1A receptor causes it to desensitize (down arrow), allowing normal firing to return (spikes). Normalized firing in the presence of reuptake blockade facilitates serotonergic transmission (up arrow). https://www.researchgate.net/figure/A-presynaptic-5HT1A-model-of-inhibitory-autoreceptor-down-regulation-in-response-to-ADT_fig4_7139099#:~:text=by%20Stephen%20Stahl- ,A%20presynaptic%205HT1A%20model%20of%20inhibitory%20autoreceptor%20down%2Dregulation%20in,at%20the%20post%2Dsynaptic%20receptor  Micro-electrode arrays (MEAs) allow us to monitor the electrical activity in neuronal networks by recording extracellularly from large numbers of neurons in a dish. 1.4 mm 1.4 mm Technology for drug testing Micro electrode array with 24 wells, each well housing an independent cell culture  Extracellular recording of action potentials Capurro A, Thornton J, Cessac B, Armstrong L, Sernagor E (2020) Nav1.7 gating in human iPSC derived sensory neurons: an experimental and computational study. BioRxiv (doi: https://doi.org/10.1101/2020.08.04.235861. Threshold sodium channels Representative channel in the testing of compound F8 (from AstraZeneca library). Bear, Mark F et al. Neuroscience: Exploring the Brain. Forth enhanced edition, 2016. Jones and Bartlett Learning, Burlington, MA. Chapter 6. Purves, D. et al. Neuroscience. Sixth edition, 2017. Sinauer Associates, Sunderland, MA. Chapter 7.