Domoic Acid, Red Tide, and Amnesic Shellfish Poisoning

Rachel Maguire, DCE 2014, primary researcher, designer, and author for this page.

Advisor Bill Heeren

Web Page Design/Template Mark Hoelzer

Numerous other people including the researchers involved in pdb file... 2PBW

This Jmol tutorial was created using the Jmol Tutorial Creator from the MSOE Center for BioMolecular Modeling.

version 1.0

Basic Overview

Domoic acid is a compound produced by phytoplankton, or algae, which is ingested when other organisms consume the algae. The acid accumulates in tissues and increases in concentration with each successive step up the food chain in a concept known as bioaccumulation. Once the acid reaches sufficient concentrations, it interacts with specific neurotransmitter receptors in the brain and causes neurological damage by interacting with some of the most basic processes of the nervous system. In humans, this neurodegeneration is referred to as "amnesic shellfish poisoning."

Note: If you're the kind of person who likes to skip to the end of stories, just go right to the jmol image. If you're the kind of person who likes to know "why?" or "how?", stick around and keep reading.

Key Concept: Bioaccumulation

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A general diagram of the concept of bioaccumulation. As you can see, the concentration of the contaminate (domoic acid, maybe, or DDT or Mercury) increases with each step up the food chain.

Basically, bioaccumulation (also known as biomagnification, biological magnification, or bioamplification) is the idea that the concentrations of a specific compound increase as you move up the food chain. In the case of domoic acid and red tide, algae produce this harmful neurotoxin which is first ingested by what are referred to as primary consumers. The primary consumers are then themselves consumed by secondary consumers and so on up the food chain. Domoic acid accumulates in fat tissues within these consumers, and with each step upward in the chain, the concentration of the acid increases, so although the concentration of domoic acid may only be 1 or 2 parts per million (ppm) in the tissues of primary consumers, by the time the domoic acid of the contaminated organisms is consumed by the highest level organisms like seals and humans, its concentration may be 20 ppm or higher which is sufficient concentration to cause neurological damage. In other words, although low concentrations in lower levels on the food chain are not immediately lethal, because domoic acid is stored in tissues, the relative concentration increases with each successive step up the food chain until it does reach levels that are harmful or lethal. This concept is not exclusive to domoic acid and red tide; in fact, it has been applied to mercury poisoning and the historically significant DDT controversy.

Structure Determines Function

Key Concept: How Neurons Conduct Messages

Neurons are made up of three basic parts, a cell body, multiple dendrites, and a single axon. The cell body is like the central hub of a neuron; it contains organelles and the nucleus. Dendrites are highly branched extensions that RECEIVE signals from the axons of neighboring cells. The axon is the long extension whose job is to SEND signals. Most cells of nervous tissue are not directly connected; instead, they have synaptic clefts between the axon and dendrites. Chemical messengers called neurotransmitters are used to transmit information across this gap.

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The Basic Structure of a Neuron

All cells have a membrane potential, but for neurons, membrane potential (the electrical difference across a plasma membrane) is integral in conducting signals, because changes in the membrane potential act as signals. In order to create and maintain a large membrane potential, neurons use active transport through the use of sodium-potassium pumps. They pump K+ ions into the cell and Na+ ions out of the cell which seems pointless; why expend energy to pump positive ions out and other positive ions in? We already know that the lipid bilayer that makes up cell membranes is selectively permeable, but equally important in the case of neurons is the fact that ion channels can also be selectively permeable. Specifically, the membrane of neurons contains selectively permeable K+ ion channels (and Na+ channels but not nearly as many) which allow only K+ ions (not any negatively charged associated anions) to pass out of the cell by passively moving down their concentration gradient. By allowing only the K+ ions to leave the cell and by using the already-present negatively charged anions within the cell, the inside of the cell eventually becomes negatively charged, and voila, a membrane potential has been created.

Other proteins embedded in the membrane, voltage-gated ion channels, open and close depending on membrane potential which is dependent on the number of K+ and Na+ ion channels open. If enough of the voltage-gated ion channels are open, a nerve impulse is created.

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Active Transport & the Creation and Maintenance of a Membrane Potential

As I alluded to earlier, neurons are not usually connected by physical channels; instead, their dendrites and axons come very close together at locations known as synapses. Communication across synaptic clefts requires the use of chemical neurotransmitters. The axon that is sending the message is referred to as the presynaptic membrane, and the dendrite that is receiving the message is referred to as the postsynaptic membrane. The presynaptic membrane contains neurotransmitters stored in synaptic vesicles. When an action potential reaches the synaptic terminal of an axon, it causes a depolarization (influx of Na+ into the cell, making the cell less negative) of the plasma membrane, causing Ca2+ ions to enter the cell, causing synaptic vesicles to fuse with the membrane and release their stored neurotransmitters which then diffuse across the synaptic cleft and bind to specific receptors embedded in the postsynaptic membrane, thereby triggering the appropriate response in the next neuron which then triggers the next neuron and so on.

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A Chemical Synapse

Glutamate Receptors

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Basic Structure of Domoic Acid
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Basic Structure of Glutamic Acid

So, what does all of this have to do with domoic acid and red tide? Well, one of those neurotransmitters is known as glutamate or glutamic acid, and it binds to glutamate receptors embedded in the postsynaptic membrane. Glutamate is an important neurotransmitter in memory and learning because when it binds to glutamate receptors, it triggers membrane channels to open, allowing Ca2+ ions to enter the cell. This influx of calcium depolarizes the membrane and causes the nerve to fire which is good and entirely necessary except for when the glutamate receptors are triggered by something other than glutamate.

At first glance, the structure of domoic acid does not look all that similar to the structure of glutamic acid, but when you consider the functional groups of the two acids, they are actually quite similar. This unfortunate fact means that glutamate receptors sometimes mistake domoic acid for glutamic acid. This means that domoic acid can trigger the same signals and the same firing of neurons that glutamic acid can. Not only that, but the ring in domoic acid reduces its flexibility which increases how tightly the acid binds to glutamic acid; as a result, the activation of glutamate receptors by domoic acid is 30 to 100 times more powerful than activation by glutamic acid.

But why, if glutamate is important in memory and learning, does an increase in activity not make an infected organisms some sort of super-genius? The reason is that domoic acid or glutamic acid, in high concentrations, are excitotoxins meaning that they literally excite nerves to death. By opening the calcium channels for extended periods of time, the neurons will burst, creating an "excitotoxic cascade" due to the release of previously stored glutamate and the production of free radicals.

These highly reactive free radicals damage the biochemical structure of just about anything they come in contact with and are shown to play an important role in brain injury and degenerative diseases.

Domoic acid specifically affects the Hippocampus portion of the brain which is crucial in the storage of new memories. Damage to this portion of the brain can leave organisms with an inability to form new memories. This memory impairment is what puts the "amnesic" in "amnesic shellfish poisoning."

How Glutamate Receptors Bind to Domoic Acid

2 Domain Structure of Glutamate Receptors
Single Domain with Domoic Acid Highlighted
Active Site of Glutamate Receptors
Amino Acids Important in Binding the Ligand
Amino Acids that Form Solvent-Mediated H-Bonds
Amino Acids that Create a Hydrophobic Cavity
All of the Above