Wednesday, September 22, 2010

Inhibiting GSK-3

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Inhibiting GSK-3

A quirky little enzyme is about to hit the bigtime.

by John McManamy

If you want to get a brain scientist excited, then simply drop the term, "glycogen synthase kinase-3," and watch him or her light up.

If you want to get yourself excited, then do something that messes with your glycogen synthase kinase-3, and watch your own brain light up.

Here’s the story: Glycogen synthase kinase-3 (GSK-3) is a type of enzyme called a kinase, or protein kinase, found inside and outside the nucleus of the cell. Protein kinases literally switch on proteins by transferring phosphate groups to them from high energy ATP molecules synthesized in the mitochondria. The process is known as phosphorylation. Phosphorylation accounts for much of the "bio" in biochemistry. Its main effect is to jumpstart cellular circuitry which in turn converts one type of energy to another.

This circuitry takes the shape of numerous types of groupings of chemicals that are variously referred to as signal transduction pathways or second messenger systems. These pathways regulate all manner of activity in the cell. Going bald? Blame it on a pathway. If a pathway or two stops functioning efficiently, then the cell is in trouble. If enough cells are in trouble, then you may be in trouble.

So far so good. From what we now know, we can assume that GSK-3 switches on signaling pathways just like the other kinases. Um, no. It turns out, through complex chemical interactions, GSK-3 actually inhibits the activity of many of the 50-odd signaling pathways it acts on. The net effect is a cell at rest.

So what happens when some neurotransmitter knocks on the cell membrane and starts sounding reveille? It turns out that our cells come well-stocked with inhibitors to the inhibitor, with no shortage of signaling pathways capable of rushing the right chemical to the scene at precisely the right moment. So when the cell is active, GSK-3, for the most part, is taking an enforced siesta.

Among many other things, GSK-3 helps regulate programmed cell death (apoptosis). Apoptosis is vital to the homeostasis (internal equilibrium) of living organisms. Here’s the paradox: through one pathway, GSK-3 promotes apoptosis while through another it inhibits the same process. If cells don’t die off the way they’re supposed to, we may end up with cancer or other auto-immune diseases. If cells die too fast in the brain, we are prone to neurodegenerative diseases such as Alzheimer’s.

Various "neurotrophic factors" responsible for the survival and growth of neurons, such as BDNF, help prevent the "mitochondrial intrinsic apoptotic pathway" from working too well. The mechanisms by which GSK-3 exerts its influence on these neurotrophic factors are not yet fully understood, but clearly very subtle. And subtle is how we want to keep things. If GSK-3’s natural inhibitors aren’t doing their job, it would be reassuring to know that we have something on hand in the medicine cabinet.

It turns out that many of us are already using a very potent GSK-3 inhibitor. It’s called lithium.
The Bipolar Connection

In 1996, researchers at the Howard Hughes Medical Institute discovered that lithium inhibited GSK-3 in cell cultures. With classic understatement, the authors of the study observed in their article: "These observations … could provide insights into the pathogenesis and treatment of bipolar disorder."

These days, the studies are coming in thick and fast. A sampling:

"Beta-catenin overexpression in the mouse brain phenocopies lithium-sensitive behaviors."

"Glycogen synthase kinase 3, circadian rhythms, and bipolar disorder: a molecular link in the therapeutic action of lithium."

"Transgenic mice overexpressing glycogen synthase kinase 3beta: a putative model of hyperactivity and mania."

"Association study of the glycogen synthase kinase-3beta gene polymorphism with prophylactic lithium response in bipolar patients."

"Full reversal of Alzheimer's disease-like phenotype in a mouse model with conditional overexpression of glycogen synthase kinase-3."

The first study on the list comes out of the lab of Husseini Manji MD at the NIMH (with Todd Gould MD as lead author). Think of depression and bipolar as more than just mood disorders. According to Dr Manji, impairments to function and cognition tend to last far beyond the course of an actual episode. Depression and bipolar may not be classic neurodegenerative diseases such as Alzheimer's, but they are clearly illnesses associated with neurons in distress.

In their study, Drs Manji and Gould explain that when GSK-3 is inhibited in the Wnt signaling pathway, more of a protein called beta-catenin is produced. In the study, one group of mice had been genetically engineered to produce extra beta-catenin. The other "normal" mice were fed either lithium or "control chow."

First, the mice were restrained to induce depression, then subjected to a forced swim test The genetic mice and the lithium mice showed little hesitation in attempting to splash their way out of their predicament whereas the control mice (to employ poetic license) displayed clear signs of melancholic indecisiveness.

Then the mice were administered amphetamine to induce mania-like behavior. Here, the results were mixed. Neither the lithium nor high beta-catenin mice displayed any observable toning down of amphetamine-induced behavior (such as biting or licking) compared to the control mice, but they did move around a lot less.

So why not just stick with our lithium and be happy with what we’ve got? As Drs Manji and Gould explain in a review article published in the Dec 2006 Current Drug Targets, current compounds leave a lot to be desired. New understanding of how the old meds work on downstream targets can lead to the development of a new generation of meds that act with greater precision (and presumably with greater efficacy and fewer side effects). In addition to lithium, antidepressants, anticonvulsants, antipsychotics, electroshock, amphetamine, estrogen, and zinc have been found to have at least some effect on GSK-3.

In their study, Manji and Gould felt sufficiently encouraged by the results to observe that: "Increasing preclinical evidence, such as that presented here, makes it likely that GSK-3 inhibitors will be utilized in bipolar disorder proof-of-concept trials."

In other words, we’ll be experimenting on rats and mice for many years to come and maybe nothing will come out of it. But a GSK-3 inhibitor is only one option. Researchers are exploring many more novel targets, and drug companies are beginning to invest in the effort. In the meantime, we have lithium and our other meds. Imperfect as they are, these pharmaceutical relics from an earlier era do somehow manage to find their way to the targets of tomorrow.

May 9, 2007, reviewed Feb 11, 2008

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