Potassium Channels Louis Colling.

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Presentation transcript:

Potassium Channels Louis Colling

function Potassium channels are channels that span cell membranes and are selective for potassium Participate in: Maintain cell volume Dampen membrane excitability Programmed cell death

Diseases Episodic Ataxia Bartter’s Disease Neuromytonia Multiple Sclerosis Rheumatoid Arthritis Diabetes Mellitus Short/long QT Syndrome Glioblastoma

types Calcium-activated Inwardly rectifying Tandem pore domain Voltage-gated

Calcium-activated Potassium channels 6T1P Three subtypes BK (large conductance) IK (intermediate conductance) SK (small conductance) Kca4/Kca5 Na+, Cl-, pH NOT Ca2+ Multiple members of the family activated are both ligand AND voltage activated, and are nonselective for Rb, Cs

Inward-rectifier Potassium channel 2T1P Three subtypes ROMK GPCR regulated ATP-sensitive Voltage-gated, close upon depolarization

Tandem pore domain 4T2P “leak channels” 15 known channels Rectifiers, regulated by Oxygen tension pH Mechanical stretch G proteins Not two-pore channels 15 known channels Contribute to resting potential

Voltage-gated potassium channels 6T1P Six general classes delayed rectifier, A-type, outward- rectifying, inwardly-rectifying, slowly activating, modifier/silencer Shaker, shab, shaw, shal, uh... Kv5, Kv6...Kv12. Beta subunits

Background Shaker potassium channels are delayed rectifier channels that primarily participate in action potentials After activation, channels enter a long-lived nonconducting state called the inactivated state These transitions are governed by physical conformational changes of the channel protein

Inside-out patch clamp

Trypsin experiments

Amino-terminal mutants

Maintenance of function mutants

Inactivation kinetics

Positively charged mutants

Point mutations

...more point mutations

Background Structural studies of membrane proteins are difficult due to the environment needed for proper assembly The interaction between the voltage-sensing domain and the pore domain are poorly understood Generalized Interaction-energy Analysis Uses molecular dynamics simulations to observe structural interactions

Simulated Kv1.2-2.1 chimera

Q-V curves

Betweenness

Canonical and proposed alternate pathway