The Newt and the Snake: An Ion Channel Arms Race

In the forests and streams of the Pacific Northwest, rough-skinned newts (Taricha granulosa) carry enough tetrodotoxin in their skin to kill several adult humans -- yet common garter snakes (Thamnophis sirtalis) eat these newts regularly and survive. The reason lies in a molecular battle happening at the level of a single protein: the voltage-gated sodium channel. Herpetologists Edmund Brodie Jr. and Edmund Brodie III have spent decades mapping this exact arms race, and it's one of the best-documented examples of coevolution driven by an ion channel blocker in the natural world.

By the end of this lesson you will be able to: explain what an ion channel is and how it generates a nerve signal; describe how tetrodotoxin (TTX) blocks voltage-gated sodium channels; explain the coevolutionary arms race between Taricha newts and Thamnophis garter snakes; and compare TTX to a second reptile neurotoxin, dendrotoxin, which blocks potassium channels instead of sodium channels.

Every nerve cell (neuron) carries signals using tiny protein gates in its cell membrane called ion channels, which open and close to let charged particles -- mainly sodium (Na+) and potassium (K+) ions -- flow in and out. When a neuron fires, voltage-gated sodium channels snap open first, letting sodium rush in and flip the cell's charge from negative to positive; this is called an action potential. A split second later, voltage-gated potassium channels open to let potassium rush back out, resetting the cell so it can fire again. This whole cycle happens in about one to two milliseconds and is how every nerve signal in a newt, a snake, or a human travels from brain to muscle.

Tetrodotoxin (TTX) is a small molecule that fits almost perfectly into the pore of a voltage-gated sodium channel, physically plugging it shut. With the channel jammed closed, sodium can't rush in, no action potential fires, and the nerve signal simply stops -- which is why TTX poisoning causes paralysis, including of the muscles used for breathing. Taricha newts produce TTX in their skin as a defense; a single newt can carry roughly enough toxin to kill 25,000 mice in lab tests. But garter snakes in the same range have evolved sodium channels with a slightly different shape at the exact spot TTX needs to bind, so the toxin can't lock on as tightly. Snakes with the most resistant channel shape can eat highly toxic newts and only feel sluggish for a few hours instead of dying.

Not every reptile neurotoxin targets the same channel. Black mambas and some other elapid snakes produce dendrotoxins, which block voltage-gated potassium channels instead of sodium channels. Since potassium channels are what reset a neuron after it fires, blocking them keeps the cell in an excited, still-firing state longer than normal, causing neurons to release extra neurotransmitter. The result is the opposite problem from TTX in one sense -- instead of silencing nerves, dendrotoxins cause overexcitation, which is part of why bites from dendrotoxin-producing snakes can cause muscle tremors and convulsions alongside paralysis from other venom components acting on different channels.