This article [Mader, 2003: (http://www.ncbi.nlm.nih.gov/pubmed/12527960)] is actually really good, and I was looking through it in more depth. I didn't used to think quantitative modeling would be useful in physiology, but it does have its value. Quantitative information is useful for getting a sense of the magnitudes of different physiological changes, as long as one doesn't expect a living organism to function in ways that are perfectly consistent with the quantitative model. Mader (2003) discussed the fact that the overall rate of glycolytic activity, encompassing the activities of all the glycolytic enzymes in the cytosol, is normally determined primarily by changes in phosphofructokinase (PFK) activity. PFK activity is increased by elevations in the free, cytosolic AMP, ADP, inorganic phosphate (Pi), and citrate, and AMP augments the ADP-mediated activation of PFK (Mader, 2003). A high intracellular, cytosolic pH (pHc) activates PFK and glycolytic activity overall, and an increase in glycolytic activity then will tend to decrease pHc. PFK activity apparently reaches 90-100 percent of its maximal rate at pHc 6.9-7.2 and above (Mader, 2003). But intracellular acidosis [a decrease in pHc to 6.2-6.4 or so (Mader, 2003), especially], decreases the rate of glycolysis to almost nothing (Mader, 2003). Mader (2003) noted that protons [acidity, meaning a high H(+), or H3O(+), concentration] inhibit PFK noncompetitively. On p. 11, Mader (2003) discusses evidence that decreases in pHc cause the creatine kinase (CK) equilibrium (I'm assuming the author is discussing the equilibrium of the cytosolic CK reaction) to favor ATP formation (cause a decrease in the PCr/ATP ratio), and this tends to be accompanied by decreases in the (cytosolic) AMP and ADP concentrations. Presumably, those decreases in the free, cytosolic AMP and ADP concentrations would tend to decrease the overall rate of glycolysis by decreasing PFK activity. Korzeniewski (2006) [Korzeniewski, 2006: (http://www.jbc.org/cgi/content/full/281/6/3057)(http://www.ncbi.nlm.nih.gov/pubmed/16314416); (http://hardcorephysiologyfun.blogspot.com/2009/08/interactions-of-acid-base-homeostasis.html)] found evidence that AMP deaminase activity helps to prevent metabolic acidosis, especially under conditions of hypoxia or during metabolic insults, by decreasing cytosolic ADP and AMP concentrations and thereby reducing glycolytic activity (which tends to decrease the pHc). Those are just some of the mechanisms that buffer the pHc. Ponticos et al. (1998) [Ponticos et al., 1998: (http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1170516&blobtype=pdf)(http://www.ncbi.nlm.nih.gov/pubmed/9501090); (http://hardcorephysiologyfun.blogspot.com/2009/05/allosteric-inhibition-of-ampk-by.html)] found that the allosteric inhibition of AMP-activated protein kinase (AMPK) by phosphocreatine (PCr) becomes less pronounced at low pH values, and it's noteworthy that AMPK also activates type 2 PFK (PFK-2) by phosphorylating PFK-2 [(Pelletier et al., 2005: (http://endo.endojournals.org/cgi/content/full/146/5/2285)(http://www.ncbi.nlm.nih.gov/pubmed/15677757?dopt=Abstract)]. That increases fructose 2,6-bisphosphate (FBP) formation by PFK-2, and FBP acts to sustain PFK activity and glycolytic activity, overall. But low pHc values might also tend to decrease AMP and ADP levels (Mader, 2003) and decrease the AMP/ATP ratio, as discussed above, and that decrease in the AMP/ATP ratio would tend to decrease AMPK activation and oppose the disinhibition of AMPK activity that would tend to occur as pHc decreases (Ponticos et al., 1998), in the face of a constant PCr concentration. A decrease in pHc would also, according to Mader (2003), tend to decrease the PCr/ATP ratio. So it sounds like acidosis could decrease the PCr-mediated inhibition of AMPK but, conceivably, also produce an opposing effect and decrease the AMP-mediated activation of AMPK. But Mader (2003) isn't really talking about an increase in ATP levels being a result of acidosis. The idea is that the equilibrium might tend to shift and to favor ATP formation, by what is basically a mass action effect of an increase in [H(+)]. It sounds to me like acidosis would tend to augment AMPK activity, and pharmacological AMPK activation sounds like it could just exert feed-forward activation of glycolysis and serve to maintain a low pHc (acidosis or borderline acidosis). Part of the idea is that AMPK activation then leads to an increase in glucose uptake and that that extra glucose will then be oxidized and buffer the pHc (increase the pHc), but there are problems with viewing things that way. It doesn't make a lot of sense, because strong, physiological (nonpharmacological) AMPK activation tends to be a result of a metabolic insult or of chronic ATP depletion, and the mitochondrial biogenesis/proliferation that tends to result from strong AMPK activation is often maladaptive and pathological (it frequently increases the formation of reactive oxygen species and leads to the formation of mitochondria that don't work properly or that exacerbate the overall degree of heteroplasmy, across all the mitochondria in the cell). Pelletier et al. (2005) noted that AMPK may not be a major factor in maintaining glycolytic activity, however, in light of experiments in mutant mice that display hypofunctional AMPK activity. AMPK also forms heterodimers (or heterooligomers, I suppose, too) with CK (Ponticos et al., 1998) and inhibits CK activity by phosphorylating it. In any case, it sounds like increases in the AMP and ADP concentrations will tend to activate glycolytic activity by various mechanisms.
Mader (2003) also discussed more research showing that the intracellular, free Pi levels are usually 2-4 mmol/kg ww muscle tissue (~ 3.3-6.6 mM), in the heart and skeletal muscles of rodents, and tend to be maintained at those low levels (as discussed in my posting yesterday). I know that hypoxia and metabolic stress are thought to increase free Pi levels in parallel with increases in AMP levels, however. That's fairly well-known. That's one hazard in relying too much on the type of modified, CK equilibrium expression that Mader (2003) offered:
[ATP] + [Pi] <---> [ADP] + [PCr] + [H(+)]
Under hypoxic or ischemic conditions, one can't really predict much by looking at mass-action effects on that multi-reaction equilibrium. And, as is apparent, Mader (2003) noted that the inclusion of [H(+)] in the CK equilibrium expression doesn't mean that H(+) directly participates in the CK reaction. The expression that Mader (2003) included (above), for the sake of deriving other relationships, is a shorthand way of showing the impact, via 12 different intervening reactions, of changes in [H(+)] on CK activity (Mader, 2003). Similarly, Katz (1988) [Katz et al., 1988: (http://www.ncbi.nlm.nih.gov/pubmed/3394819)] used this expression:
PCr ---> Cr + Pi + (s)H(+), where (s) = 0.63 - [(pHcytosolic - 6.0)(0.43)]
Those two expressions don't make much sense to me, though, because they're superficially contradictory. In any case, it's not necessary to get bogged down in the details of deriving simple, equilibrium expressions that may not predict in vivo changes. The "equilibrium" that Katz et al. (1988) was using (above) is not really an equilibrium, though, because it's showing multiple enzymatic reactions, and so is the expression that Mader (2003) uses. Also, Mader (2003) is referring to free, cytosolic [Pi], and it's not clear to me that Katz (1998) is referring to cytosolic or free [Pi]. Lyoo et al. (2003) referred to the same expression that Mader (2003) used, essentially [except Mader (2003) replaced [Cr] with [Pi] (that's like saying they're on the same side of the equilibrium expression but that removing [Cr] from the expression simplifies it), because of various assumptions]:
[Cr] + [ATP] <---> [PCr] + [ADP] + [H(+)] (Lyoo et al., 2003)
Or maybe [H(+)] should be viewed as being a kind of "floating" element, in the equilibrium, that influences the PCr/ATP ratio and other ratios in different ways under different circumstances. Here's my composite expression (this may or may not have validity, but the contradictions in the various expressions, as presented above, are not pleasing for me to see):
[H(+)] <---> ... <---> [Cr] + [Pi] + [ATP] <---> [PCr] + [ADP] <---> ... <---> [H(+)]
In any case, some of those articles are interesting.
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