Tuesday, January 06, 2009

Chinese food, umami, autism, schizophrenia, and cancer

There's a fascinating interrelationship among the things mentioned in the title – and it takes us through equally fascinating topics in molecular cell biology and neurobiology.

No, Chinese food has not been found to cause the listed maladies – although with the additives that the People's Republic of China seems to be allowing in many of its food products these days (e. g. melamine), who knows for sure?

So what's the connection? Try monosodium glutamate (MSG). That, of course, is the sodium salt of glutamic acid (which itself is often referred to as "glutamate"). MSG is a rather well known food additive which at one time was very commonly used in Chinese food for its ability to "enhance" flavor. Technically, the form of glutamate responsible for flavor is the ionic form rather than the sodium salt – the former being what is found in aqueous solution rather than the latter dry crystalline form.

MSG became notorious some time ago when Chinese food became popular in western countries, because it was at first unfamiliar and also tended to cause headaches or at least a peculiar lightheaded sensation after eating food to which it had been added. Consequently, most Chinese restaurants, at least in the U. S., now carefully inform customers that their food "contains no MSG".

Nevertheless, it's impossible to escape glutamate, because glutamic acid is one of the 20 amino acids that make up all proteins. It's essential to life as we know it, and so in fact it can't be avoided.

It also happens to be one of the most important neurotransmitters, and in that role is absolutely essential to the function of animal nervous systems. This role of glutamate is the key part of the story here.

As a flavor, glutamate is responsible for the much hyped "fifth taste" known in Japanese as umami. The first four basic tastes are sweetness, bitterness, sourness, and saltiness. Each of these is detected by specialized receptors on human tongues. Like the others, umami is also detected by its own receptor, but what's actually being detected is the amino acid glutamate present in all protein-containing foods, especially meats, cheese, and soy products.

Although the flavor is enjoyable, it's as a neurotransmitter that glutamate is important for the present story. As a neurotransmitter, glutamate is excitatory. In fact, it's the most abundant excitatory neurotransmmitter in mammalian nervous system. An electrical impulse traveling down a neuron's axon triggers the release of glutamate at the presynaptic side of glutamate synapses. When this glutamate is picked up by receptors at the other side (the postsynaptic side) of the synapse it contributes to possible excitation of the postsynaptic neuron. This is the basic mechanism by which signals are transmitted through an animal's nerves. (But there are other neurotransmitters besides glutamate that may be involved.)

However, this excitatory behavior can get out of hand, and when it does glutamate can have a toxic effect, called excitotoxicity. This can kill neurons and cause disease conditions such as autism, schizophrenia, and epilepsy.

Since glutamate is both essential but also (in excessive amounts) potentially toxic, an elaborate negative feedback system has evolved to keep glutamate production and release under careful control. It is when this feedback system fails somehow that neurological diseases develop. A typical cause of failure is mutation of genes that produce proteins essential to the feedback system.

So what are some of these genes/proteins? The first of these is the metabatropic glutamate receptor, mGluR for short. This is a receptor found on the surface of an axon, close to a glutamate synapse. When glutamate outside the neuron binds to such a receptor, it acts to tamp down the exited state of the neuron that led to release of glutamate in the first place. This process is called autocrine signaling, meaning that it involves a cell releasing a signaling molecule that can trigger a receptor on the same cell to modify cell behavior. This is the start of the negative feedback loop.

One source of failure is in mutation of mGluR itself, if this mutation causes further steps in the feedback loop to fail. What are some of these further steps? The first and possibly most important involves a protein enzyme with the charming name of PI3K. That's short for "Phosphoinositide 3-kinase", and we should be grateful for not having to write it out in full every time.

PI3K is a kinase, which means its enzymatic action is to cause phosphorylation of other proteins. A sequence of phosphorylating kinsaes constitutes a signal cascade or "pathway".

PI3K is the start of a pathway that plays a huge role in cell survival and proliferation – among other things. Clearly, it's an important protein.

The next step in the pathway is another kinsase called AKT. It's actually, in humans, a small family of proteins, Akt1, Akt2, and Akt3. Akt1 is the main player. One of its main jobs is cell survival, as an inhibitor of apoptosis. There are many reasons, both good and bad, for a cell to die by apoptosis. Akt1 is there to prevent the bad reasons for being responsible for too much cell death.

However, in cells that have become cancerous, one or another member of the AKT family typically functions only too well, resulting in the uncontrolled proliferation of cells that is the hallmark of cancer. In fact, an AKT kinase is hyperactive in the majority of human cancers. These molecules have been called perhaps the most frequently activated type of oncoprotein. (Reference: here.) Not only is AKT, in one form or another, involved in a majority of cancers, in many types of cancer, some form of AKT is a key factor. For instance, in melanoma, the interaction of Akt3 and another important cancer-related protein, c-Raf, is involved in 60-70% of melanoma-related tumors. (Reference: here.)

Not too long ago we discussed several other kinases (mTOR and MAP kinases), as well as PI3K and AKT, that play a role in cancer.

Its significant involvement in cancer is far from the only reason AKT is interesting, though. It is a versatile kinase involved in multiple pathways. In particular, it also participates in the negative feedback loop for glutamate because it deactivates a FoxO transcription factor. (For many details on that topic, see here.)

Now we're really getting into the heart of the story on the negative glutamate feedback loop. Recent research on fruit fly motor neurons, which we're about to refer to, suggests (among other things) that an AKT kinase inhibits a FoxO transcription factor that otherwise would stimulate glutamate release.

In a nutshell, the autocrine stimulation of the mGluR glutamate receptor activates PI3K, which activates an AKT kinase, which then inhibits a transcription factor, thereby inhibiting further glutamate release. This negative feedback loop keeps motor neurons from becoming overactive.

Here's a picture of what's going on:

Any mutation of the signaling kinases involved in this feedback loop would, of course, destabilize the control mechanism, but would likely cause other pathology as well, because of the involvment of PI3K, AKT, and FoxO in many other important cellular processes. However, if it was the mGluR glutamate receptor that was affected by a mutation, the main consequence would be some neurological pathology such as epilepsy.

A further reasonable speculation would be that mutations affecting mGluR in other types of neurons could cause other neurological problems, such as autism or schizophrenia. The present research does not actually deal with this more general case. However, other research has implicated PI3K and mGluRs in epilepsy, neurofibromatosis (a type of non-cancerous tumor), autism, schizophrenia, and other neurological disorders in humans.

Here's the research and its abstract:

A PI3-Kinase–Mediated Negative Feedback Regulates Neuronal Excitability
Use-dependent downregulation of neuronal activity (negative feedback) can act as a homeostatic mechanism to maintain neuronal activity at a particular specified value. Disruption of this negative feedback might lead to neurological pathologies, such as epilepsy, but the precise mechanisms by which this feedback can occur remain incompletely understood. At one glutamatergic synapse, the Drosophila neuromuscular junction, a mutation in the group II metabotropic glutamate receptor gene (DmGluRA) increased motor neuron excitability by disrupting an autocrine, glutamate-mediated negative feedback. We show that DmGluRA mutations increase neuronal excitability by preventing PI3 kinase (PI3K) activation and consequently hyperactivating the transcription factor Foxo. Furthermore, glutamate application increases levels of phospho-Akt, a product of PI3K signaling, within motor nerve terminals in a DmGluRA-dependent manner. Finally, we show that PI3K increases both axon diameter and synapse number via the Tor/S6 kinase pathway, but not Foxo. In humans, PI3K and group II mGluRs are implicated in epilepsy, neurofibromatosis, autism, schizophrenia, and other neurological disorders; however, neither the link between group II mGluRs and PI3K, nor the role of PI3K-dependent regulation of Foxo in the control of neuronal excitability, had been previously reported. Our work suggests that some of the deficits in these neurological disorders might result from disruption of glutamate-mediated homeostasis of neuronal excitability.

Further reading:

Possible Clues To Root Of Epilepsy, Autism, Schizophrenia (12/9/08) – press release

Eric Howlett, Curtis Chun-Jen Lin, William Lavery, Michael Stern (2008). A PI3-Kinase–Mediated Negative Feedback Regulates Neuronal Excitability PLoS Genetics, 4 (11) DOI: 10.1371/journal.pgen.1000277

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