Magnesium, a second messenger for insulin: Ion translocation coupled to transport activity

1. 1.|Magnesium ion, it is proposed, can serve as a second messenger for insulin. 2. 2.|When hemi-uteri from ovariectomized rats are incubated in modified Krebs-Henseleit solution, the following findings are obtained: (a) This muscle maintains a substantial concentration gradient, relative to the medium for both Mg 2+ and K +. (b) Insulin added in vitro gives a net increase in accumulation of Mg 2+ and K + (7–16%). (c) Ouabain (5 × 10 −4 M), a specific inhibitor of (Na + + K +)-ATPase, gives rise to striking changes in intracellular ion content. As expected, Na + rises and K + falls. Mg 2+ increases to a level as high as that obtained with insulin in the absence of ouabain, and no additional increase in Mg 2+ content is found when insulin is added in the presence of ouabain. Omission of K + from the medium in part mimics the ouabain effect. The insulin stimulation of Mg 2+ accumulation therefore is dependent on an actively functioning (Na + + K +)-ATPase system. 3. 3.|These data, taken together with other definitive studies on amino acid transport and glucose transport, constitute the basis for the following proposal: When insulin interacts with its receptor, perturbations emanate from this site to adjacent regions, there to activate, selectively, membrane-situated transport systems, including (Na + + K +)-ATPase. In the course of these events, Mg 2+, a critical second messenger, is translocated to responsive intracellular loci. 4. 4.|The interactions of insulin and epinephrine are discussed in terms of interactions between their specific receptors and enzymes that generate second messengers.