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:6TM2 TM4TM

Evolutionary tree does notcluster 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 formerdrives repolarization while the later spaces successiveAP more widely. Each act to dampen excitability.

3 types of KCa:BK, Maxi KIK, fast AHPSK, slow AHP

Why are state kineticdiagrams so complexfor this type of calcium-activated channel?

Spike FrequencyAdaptation =

Membranes may hyperpolarize twiceand different KCa

channels drive the slow and fast component.

Called = Phasic FiringPatterns

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 theCalcium Action Potential

What is a CalciumSpike?

Calcium Shapes theRegenerative A.P.

And is in EVERY excitable cell.

Internal Calcium: Three Best Studied Roles =

1. Contraction of Muscle2. Secretion3. Gating

Why is calciumsaid to be TheIon?

How does it act to be A Second Messenger?

Calcium-dependent Exocytosis - Neurotransmittersand Digestive Enzymes

Probability of NTrelease is proportionalto [Ca]3.9

2 Sources of Calcium:1. PM Ca Channels2. Intracellular

Storing Organelles

100s of Docking Associated Proteins!

Resting Calcium ConcentrationIn most cells:

30 – 200 nM

Increases in calcium measuredwith fluorescent Caindicators = small rise and slow fall…..

Is this what physiologicallyoccurs?

A. 1970s Llinas = HVA and LVAB. 1988 Tsien = T and L typeC. 1990s Pharmacology = P/Q, N, and R typeD. 2000 Molecular = Structural Architecture

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

Physiological time courseof Inactivationof calcium channelsis likely much shorter thanbiophysicalexperiments…..

Due to high useof barium to visualize the smallcurrents.

2 Pulse: To allow the internal Caentry and then measure fraction of Ca channels that are inactivated.