Kinases turn the power on, phosphatases turn it off

A little work coming out on phosphatases is interesting.

Although most of the background information in this article is freely available in other articles at this site, we will begin with a little review.

Broad Principle: Chemicals in the body sit inert unless activated by a high energy phosphate bond (PO4-), which typically comes from ATP, but can come from similar carriers of the phosphate. Phosphate bonds have electrons to provide, without which the chemicals may as well not even be there. Hence, if something is phosphorylated, it is ready to go. If the phosphate is removed, however, the chemical goes back to deep storage. Eat all the sugar you can hold and you cannot digest it until a kinase comes along and turns it into glucose-6-phosphate. You get the picture. The same thing applies to pain chemicals. Sticks and stones will break my phones, but dephosphorylated pain chemicals can never hurt me.

Review Principal: Capsaicin excites the TRPV-1 receptor, a pain receptor involved with calcium currents in pain nerves. Originally the TRPV-1 receptor was known as the vanilloid-1 receptor because vanilloids, such as the cannabinoids, bound to it. Pain relief work on cannabinoids is now primarily done on the cannabinoid2 receptor (CB2), which seems a promising avenue of research for pain blocking. With or without resort to CB2, the pain chemicals cannot act unless a battery in the form of a high energy phosphate bond is attached. Protein phosphatases can remove the battery, so they are interesting molecules for researchers in this area.

The attaching of high energy phosphates is done by kinases. The removal of high energy phosphate bonds is done by phosphatases. We have written a great deal about kinases, particularly tyrosine kinase A, or TrkA, which is found only in PAIN neurons. We hope to see a cell killer which can kill any cell which contains TrkA, as a treatment for pain. When NMDA is set off by calcium flow at the synapse, kinases kick into gear to activate receptors and pain is the result.

In the normal person, not experiencing pain, the attaching and removal of high energy phospates is done by the balancing of kinases and phosphatases.

Now, Zhang, et al in Mol Pain. 2006 Mar 20, have focused on a specific phosphatase, protein phosphatase 2A (PP2A), specifically “serine/threonine protein phosphatase type 2A (PP2A) on the central nociceptive amplification process, which is induced by intradermal injection of capsaicin in rats.”

Zhang is out of the program of Wm Willis Jr, a correspondent and one of the early leaders of the pain brain trust from UTMB. There is some Country and Western song about “When I die I hope to go to Texas” and if you have pain this song makes sense, thanks to the wonderful work done by Bill Willis and Claire Hulsebosch, who continue to turn out great pain scientists. This author felt he was finally able to read the pain literature when he managed to understand an early Wm Willis Jr. text. That was many years ago, and Dr. Willis, an immensely nice person, (in one of his books he write how hard it was for him to give central pain to rats and watch them suffer) is still at it. Now, we try to understand the articles being written by his graduate students. What thanks are adequate to Dr. Willis we cannot imagine.

When capsaicin is injected, there is immediate upregulation of PP2A. This is part of the mechanisms whereby central modulation of phosphorylation is “strictly controlled and balanced by the opposing activities of protein kinases and phosphatases”.

When capsaicin was injected, there was of course a significant decrease in the exploratory activity of rats. This is probably because muscle pain is part of central pain, and also because when we are in pain, unless we can see that activity will take us out of it, we tend not to move around. We don’t feel well.

When the PP2A was blocked with okadaic acid or fostriecin in the spinal fluid, the exploratory activity resumed after about thirty minutes, presumably demonstrating that the activation of pain chemicals by kinases had resumed.

As regards therapy, this suggests a powerful new way in which pain might be blocked. If we could enhance PP2A, we might be able to block activation of pain proteins by kinases.