Regulation of Ion Channels by Drugs and Hormones
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Transcript of Regulation of Ion Channels by Drugs and Hormones
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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
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Adrenergic Regulation of Cardiac Electrical Activity:
Lessons from Human Disease
Keating & Sanguinetti, Cell, 2001.
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LQTS: Genetic Linkage to Multiple Ion Channel Genes
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AP Prolongation Can Trigger Arrhythmias
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Triggers Are Gene-specific
Circ 2001;103:89-95
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-Adrenergic Stimulation Shortens AP Duration
(Kass & Wiegers, J Physiol. 1982)
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-AR Regulation of Cardiac AP:A Balance of Inward and Outward
Current
• L-type Calcium Channel current Increased
• Slow IKs potassium channel Current Increased
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KCNE1KCNQ1 (KvLQT-1)
KCNQ1+KCNE1
200 pA/pF
KCNQ1
0.5 s
50 pA/pF
(Splawski et al, Circ102;1178-85, 2000)
(minK)
Molecular Architecture of IKS Channel Revealed Through LQTS studies
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Receptor stimulation to Local Signaling
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Agonist Binding and Receptor Activation
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cAMP Pathway: Receptor Activation Increases cAMPi
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cAMP Bindng: Dissociation of Regulatory and Catalytic PKA subunits
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Adaptor Proteins:
Molecular Basis for Receptor/Substrate Diversity: Channel as
Macromolecular Complexes
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Calcium Channel Complex
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Channels as Macromolecular Signaling Complexes
• Signaling Microdomains exapnd diversity of receptor-mediated cellular responses
• Disruption of Microdomains in disease can unbalance physiological responses
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K Channel Complex
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-40 -20 0 20 40 60 80
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8Br-cAMP
Tai
l cu
rren
t (p
A/p
F)
Pre-pulse potential (mV)
control cAMP
mouse CHO cell0
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Incr
ea
se
of
tail
I Ks
Iso
8Br-cAMP
OA+8Br-cAMP
OA
Functional regulation in TG+ Myocytes but not in CHO cells:Phosphatase and Kinase activity
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Human Heart
KCNQ1 forms a macromolecular complex
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RyR macromolecular complexes are held together by
leucine/isoleucine zippers (LZs)
Marx, et al., (2001). The Journal of Cell Biology, 153: 699-708.
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A leucine zipper motif in KCNQ1 C-terminus :Coordination of protein-protein interactions
(LZm = V595A/L602A)
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The K channel Complex can be Disrupted in Disease
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AP Prolongation Can Trigger Arrhythmias
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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 Physiology 69, 497-515.
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Sodium and Calcium Channels are Targets of Voltage-Regulated Drugs
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Drug Ionization Restricts Access to Drug Receptor
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Na+ Na+
Na+
X
Closed Open
Inactivated
Na+ channel open state inactivation
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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.
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Drug binding is influenced by the state of the channel:
Preferential binding to and Stabilization of the Inactivated State
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Block Develops During Repetitive electrical Activity
• Block During Depolarization (systole)
• Unblock During Repolarization (Diastole)
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Mapping a drug receptor via Alanine Scanning
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Targeting Different Channels for Distinct Therapeutic Goals:
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50msKPQ
Chandra, R., et. al., (1998) Am. J. Physiol. 274, H1643-H1654.
Wild-Type (WT) Y179C (YC)
Novel Pharmacology of Inherited Sodium Channel Mutations
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The Local Anesthetic Receptor for Voltage-Gated Sodium Channels
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