Diversity of Form and Function of Voltage- Gated Potassium Channels

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Presentation transcript:

Diversity of Form and Function of Voltage- Gated Potassium Channels 80 Family Members 5 Architectures 3 Gene SubFamilies Classes to highlight function: 1. Shaker 2. KCa 3. KIR

3 Gene SubFamilies: 6TM 2 TM 4TM Evolutionary tree does not cluster by architecture and architectures do not align to specific function.

Frequency-modulated code = The stronger the injected current, the higher the rate of AP frequency

IK vs. IA: Function can be separated not only pharmacologically, but physiologically by Vh. The former drives repolarization while the later spaces successive AP more widely. Each act to dampen excitability.

3 types of KCa: BK, Maxi K IK, fast AHP SK, slow AHP Why are state kinetic diagrams so complex for this type of calcium-activated channel?

Spike Frequency Adaptation = Membranes may hyperpolarize twice and different KCa channels drive the slow and fast component. Called = Phasic Firing Patterns

Bursting Pacemaker Electrical Activity

KIR: The anomalous rectifiers

Ih can increase cardiac pacemaker activity

Cl Channels are currently classified according to the activating stimulus to gate the channel, rather than by molecular structure

Fatt and Collaborators: First discovery of the Calcium Action Potential What is a Calcium Spike? Calcium Shapes the Regenerative A.P. And is in EVERY excitable cell.

Internal Calcium: Three Best Studied Roles = Contraction of Muscle Secretion Gating Why is calcium said to be The Ion? How does it act to be A Second Messenger?

Calcium-dependent Exocytosis - Neurotransmitters and Digestive Enzymes Probability of NT release is proportional to [Ca]3.9 2 Sources of Calcium: PM Ca Channels Intracellular Storing Organelles 100s of Docking Associated Proteins!

Resting Calcium Concentration In most cells: 30 – 200 nM Increases in calcium measured with fluorescent Ca indicators = small rise and slow fall….. Is this what physiologically occurs?

1970s Llinas = HVA and LVA 1988 Tsien = T and L type 1990s Pharmacology = P/Q, N, and R type 2000 Molecular = Structural Architecture

Therefore the nominclature following molecular era is still a mix of phenomenological and cloning classification!

Physiological time course of Inactivation of calcium channels is likely much shorter than biophysical experiments….. Due to high use of barium to visualize the small currents. 2 Pulse: To allow the internal Ca entry and then measure fraction of Ca channels that are inactivated.