Helen Brew Ph.D. Research Assistant Professor hbrew@u.washington.edu

Four subunits make up a doughnut-shaped protein pore that lets electric currents flow in and out of nerve cells. Bruce’s lab made mice that lacked one of these proteins, Kv1.1, and they turned out to be epileptic. Presumably, some neurons electric currents changed, making them easily overstimulated and leading to seizures. There are also Kv1.2 knockout mice in the lab, and they seem abnormally resistant to stimulation, suggesting that these very similar sister proteins may play different roles.

Out of the forty thousand-ish or so proteins that construct mammals, it turns out that this Kv1.1 protein is the ONLY one targeted by a particular toxin compoent of black mamba venom, dendrotoxin-K (DTX-K). Another venom component, DTX-I targets both Kv1.1 and its sister subunits Kv1.2 and Kv1.6. Interestingly, when DTX-I gets into the CNS, it causes seizures. (However, peripheral effects of black mamba venom would probably kill us first anyway…..).

Most of the Kv1.1 and Kv1.2 subunits in our bodies are found colocalized beneath the insulation material (myelin) of our nerve cables (axons). This suggests that together they may form pores particularly suited to ensuring that nerve conduction works properly. However, some scientists claim that they are usually so electrically isolated beneath the insulation that they’re not doing much, unless the myelin is disrupted…..e.g. in multiple sclerosis.

Some auditory neurons have particularly powerful Kv1 currents that may be “naked” of myelin, and important for ensuring that auditory neurons transmit information as faithfully as axons. (When our brains receive signals from our ears, or send a signal to our muscles, we don’t want our axons to degrade that information!). We hope to find out what different combinations of Kv1.1 and Kv1.2 and other Kv1 subunits occur in auditory neurons, and what types of currents flow as a result, using the knockout mice as a test bed. We also want to know what controls the movement of Kv1 electrical pores to particular parts of neurons such as the axons.

Where flies have one potassium channel subunit gene, we and other mammals have 8 or more genes called Kv1.1 up to Kv1.8. So why didn’t we make do with just one?

Each channel needs four of these subunits, so perhaps it’s to increase the possible types of channel? Or to finetune the exact channel properties…..? And allow differential regulation of different types of channels?

OOOooooooooor……perhaps we were trying to evolutionarily outrun the black mamba?!