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Regulation of Ion Channels by Drugs and Hormones

Regulation of Ion Channels by Drugs and Hormones. Roles of local signaling complexes Lessons from Investigation of Human Disease Pharmacology Unique to Voltage-Gated Ion channels. Adrenergic Regulation of Cardiac Electrical Activity : Lessons from Human Disease.

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Regulation of Ion Channels by Drugs and Hormones

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  1. Regulation of Ion Channels by Drugs and Hormones • Roles of local signaling complexes • Lessons from Investigation of Human Disease • Pharmacology Unique to Voltage-Gated Ion channels

  2. Adrenergic Regulation of Cardiac Electrical Activity:Lessons from Human Disease Keating & Sanguinetti, Cell, 2001.

  3. LQTS: Genetic Linkage to Multiple Ion Channel Genes

  4. AP Prolongation Can Trigger Arrhythmias

  5. Triggers Are Gene-specific Circ 2001;103:89-95

  6. -AdrenergicStimulation Shortens AP Duration (Kass & Wiegers, J Physiol. 1982)

  7. b-AR Regulation of Cardiac AP:A Balance of Inward and Outward Current • L-type Calcium Channel current Increased • Slow IKs potassium channel Current Increased

  8. KCNQ1 (KvLQT-1) KCNE1 (Splawski et al, Circ102;1178-85, 2000) KCNQ1 KCNQ1+KCNE1 50 pA/pF 200 pA/pF 0.5 s Molecular Architecture of IKS Channel Revealed Through LQTS studies (minK)

  9. Receptor stimulation to Local Signaling

  10. Agonist Binding and Receptor Activation

  11. cAMP Pathway: Receptor Activation Increases cAMPi

  12. cAMP Bindng: Dissociation of Regulatory and Catalytic PKA subunits

  13. Adaptor Proteins: Molecular Basis for Receptor/Substrate Diversity: Channel as Macromolecular Complexes

  14. Calcium Channel Complex

  15. Channels as Macromolecular Signaling Complexes • Signaling Microdomains exapnd diversity of receptor-mediated cellular responses • Disruption of Microdomains in disease can unbalance physiological responses

  16. K Channel Complex

  17. cAMP control 5 Iso 8Br-cAMP 4 5 10 control OA+8Br-cAMP 8Br-cAMP 8 3 OA Increase of tail IKs 6 9 2 Tail current (pA/pF) 5 4 5 7 2 1 0 0 -40 -20 0 20 40 60 80 mouse CHO cell Pre-pulse potential (mV) Functional regulation in TG+ Myocytes but not in CHO cells: Phosphatase and Kinase activity

  18. KCNQ1 forms a macromolecular complex Human Heart

  19. RyR macromolecular complexes are held together by leucine/isoleucine zippers (LZs) Marx, et al., (2001). The Journal of Cell Biology, 153:699-708.

  20. A leucine zipper motif in KCNQ1 C-terminus : Coordination of protein-protein interactions (LZm = V595A/L602A)

  21. The K channel Complex can be Disrupted in Disease

  22. AP Prolongation Can Trigger Arrhythmias

  23. State-dependent Block of Ion Channels by drugs • The Modulated Receptor Hypothesis • Hille, B. (1977). Local anesthetics: hydrophilic and hydrophobic pathways for the drug-receptor reaction. Journal of General Physiology69, 497-515.

  24. Sodium and Calcium Channels are Targets of Voltage-Regulated Drugs

  25. Drug Ionization Restricts Access to Drug Receptor

  26. Na+ Na+ Na+ X Closed Open Inactivated Na+ channel open state inactivation

  27. Use-Dependent Block • Pulse-dependent channel availability depends on recovery from inactivation; • Drug-Bound Channels recovery slower than drug-free channels; • Channels are not available for excitation when drug-bound.

  28. Drug binding is influenced by the state of the channel: Preferential binding to and Stabilization of the Inactivated State

  29. Block Develops During Repetitive electrical Activity • Block During Depolarization (systole) • Unblock During Repolarization (Diastole)

  30. Mapping a drug receptor via Alanine Scanning

  31. Targeting Different Channels for Distinct Therapeutic Goals:

  32. Wild-Type (WT) Y179C (YC) DKPQ 50ms Chandra, R., et. al., (1998) Am. J. Physiol. 274, H1643-H1654. Novel Pharmacology of Inherited Sodium Channel Mutations

  33. The Local Anesthetic Receptor for Voltage-Gated Sodium Channels

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