Allosteric Inhibition of AMPK by Phosphocreatine; Inhibition of Creatine Kinase Activity by AMPK

This article is interesting [Ponticos et al., 1998: (http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1170516&blobtype=pdf)(http://www.ncbi.nlm.nih.gov/pubmed/9501090)], and the authors show that the activity of the purified, muscle-specific isoform of creatine kinase is inhibited significantly upon its phosphorylation by AMPK. The other main findings are that creatine kinase binds to (i.e. heterodimerizes or forms heterooligomers, given that the stoichiometry of the interaction is unknown) AMPK, that phosphocreatine inhibits AMPK activity, that creatine reverses that inhibition, and that the inhibition by phosphocreatine becomes more pronounced as the pH increases, within physiological pH ranges. Assuming that these effects are not going to be attenuated in situ (in a living organism, "in place"), these are really important findings and provide more evidence (fairly devastating evidence) that pharmacological AMPK activation, such as by AICAR, is really not a good idea, in my opinion. The inhibition of creatine kinase activity, by 60 percent, upon its phosphorylation by AMPK, is not likely to be a desirable effect, under many conditions, in my opinion. The effects of AICAR on the liver and on metabolism in general can be very bad. That's just my opinion, and I've discussed this in past postings. AMPK activation increases glycolytic activity, and that's invariably going to tend to intensify the acidosis, especially under the conditions of diminished respiratory chain activity that are likely to exist in the cells of people who are supposedly going to benefit from AICAR. So how is AMPK activation really going to cause a "cycling" back up toward a high phosphocreatine/creatine ratio (as discussed in the article)? It might, in the context of something like recovery from high-intensity exercise, in which the profligate supply of lactate, free fatty acids, ketones, and other energy substrates will tend to restore the ATP/AMP ratio and preclude the development of the kind of mitochondrial pathology that tends to result, in my opinion, from chronic, pharmacologically-mediated activation of AMPK. But the ends don't always justify the means, particularly when it comes to the regulation of glucose transport by AMPK. Increasing glucose transport at any cost, such as by pharmacologically-mediated AMPK activation, is a legitimate goal, but it's not possible, in my opinion, to address and ameliorate profound pathologies in energy metabolism by only pharmacological means. It tends to be necessary, in my opinion, to make some attempt to restore the actual metabolic activity, instead of only using pharmacological stopgap measures. It should tell people something that insulin generally decreases AMPK activity [Hue et al., 2003: (http://www.biochemsoctrans.org/bst/031/0213/bst0310213.htm); countless other articles]. Here's an article that shows that a decrease in AMPK activation during experimental ischemia (in a model of ischemic stroke) in mice lessened the damage due to ischemia. The article also shows that AICAR worsened the damage [McCullough et al., 2005: (http://www.jbc.org/cgi/content/full/280/21/20493)(http://www.ncbi.nlm.nih.gov/pubmed/15772080?dopt=Abstract)]. That's only under acute conditions, too. All of the responses that are supposed to neatly occur in the longer term, following AMPK activation, also just don't seem to show up, in my opinion, as reliably as one might expect them to show up.