Magnesium, Mast Cells, Histamine, and Adrenergic "Mast Cell Stabilization"

This article shows that magnesium depletion acutely increases histamine release from mast cells in a dramatic fashion [Kraeuter and Schwartz, 1980: (http://jn.nutrition.org/cgi/reprint/110/5/851) (http://www.ncbi.nlm.nih.gov/pubmed/6445415?dopt=Abstract)]. Although those authors found that the histamine levels decreased subsequently, the increased numbers of mucosal or submucosal mast cells persisted. That in itself is not desirable, given that mast cells release many other pro-inflammatory substances other than histamine. Those substances include all sorts of cytokines, such as tumor necrosis factor-alpha, and proteases that tend to degrade the extracellular matrix and lead to secondary inflammatory processes, etc. Mast cells are present at many sites in the body and contribute to lots of disease processes.

That article isn't the best example, and the sheer numbers of articles on magnesium complicate the task of organizing the articles. The overall idea that's been shown in many articles is that magnesium decreases histamine release from mast cells by essentially acting as a calcium channel antagonist, given that calcium influx into mast cells causes the histamine-containing storage granules (and other protein mediators, such as cytokines and proteases) to undergo exocytosis (degranulation). Magnesium decreases calcium influx and buffers calcium influx, and this tends to decrease histamine release. Mast cells can also undergo piecemeal degranulation and release small amounts of mediators slowly, and the increases in numbers of mast cells, as observed in chronic magnesium deficiency (Kraeter and Schwartz, 1980), could reasonably be expected to increase piecemeal degranulation. Mast cells have been heavily implicated in atherosclerotic progression, and magnesium has strong effects on the dynamics of histamine release from mast cells. Histamine release also depletes intracellular magnesium from red blood cells (RBC) (I have the article on my computer but am not up for organizing references right now), and the effect is dramatic enough to be detectable in humans in vivo (upon the extraction of RBC).

Another layer to this is the capacity of adrenergic activity (catecholamine release, catecholaminergic transmission in the brain and peripherally) to deplete intracellular magnesium from various cell types but to simultaneously, via beta2-adrenoreceptor activation, in particular, "stabilize" mast cells (i.e. decrease histamine release, stabilize the "loose-cannon" aspect of mast cell degranulation). Beta2-adrenoreceptor agonists, used in asthma, are known to produce this effect, and a similar effect can occur in response to something like pseudoephedrine, taken during a cold or for allergies, etc. But catecholaminergic activity, such as beta2-agonists "mediate" (they bind to receptors for noradrenaline/adrenaline), depletes magnesium from numerous cell types. This tends to lead to decreases in magnesium availability to mast cells, and the catecholamine-mediated depletion of magnesium may limit the "mast-cell-stabilizing" effects of adrenergic activity, in the long term. Exercise increases catecholaminergic transmission, and high-intensity exercise, such as resistance exercise (weights), can drastically increase it. That's one mechanism by which exercise can produce, particularly in the absence of some sort of attempt to compensate for the effect, intracellular magnesium depletion. Magnesium also tends to directly decrease catecholaminergic activity or buffer catecholamine release, and this tends to be desirable in the context of something like exercise. One reason has to do with the fact that massive catecholamine release from sympathetic nerve terminals, such as during intense exercise, can derange the autoreceptor-mediated regulation of the firing rates of the adrenergic neurons. That's one imprecise explanation, but magnesium can also enhance adenylate cyclase activity somewhat and influence adrenergic activity by that mechanism or by the preservation of adenine nucleotide pools intracellularly, etc. One of the direct mechanisms responsible for the capacity of magnesium to decrease catecholamine release is that calcium influx is an important mechanism that regulates neurotransmitter release. But the presence of an adequate pool of magnesium can actually potentiate catecholaminergic transmission, in the context of the long-term "hypersympathetic" bias that tends to occur as people age, or influence the extents to which different receptor subtypes are activated and thereby "improve" or normalize adrenergic transmission. That's relatively imprecise, but a sustained and persistent increase in adrenergic activity tends to be detrimental to the regulation of adrenocorticotropic hormone (ACTH) release and to the feedback inhibition of corticotropin releasing hormone (CRH) release from different cell groups in the brain, etc.