Amarcord: I Remember

Abstract

Ja, Kalzium, das ist alles!-Otto Loewy (1959)I have tried to offer a historical account of a success story, as I saw it develop from the early times when it interested only a few aficionados to the present times when it has pervaded most of cell biochemistry and physiology. It is of course the story of calcium signaling. It became my topic of work when I was a young postdoctoral fellow at The Johns Hopkins University. I entered it through a side door, that of mitochondria, which had been my area of work during my earlier days in Italy. The 1960s and 1970s were glorious times for mitochondrial calcium signaling, but the golden period was not going to last. As I have discussed below, mitochondrial calcium gradually lost appeal, entering a long period of oblivion. Its fading happened as the general area of calcium signaling was instead experiencing a phase of explosive growth, with landmark discoveries at the molecular and cellular levels. These discoveries established that calcium signaling was one of the most important areas of cell biology. However, mitochondria as calcium partners were not dead; they were only dormant. In the 1990s, they were rescued from their state of neglect to the central position of the regulation of cellular calcium signaling, which they had once rightly occupied. Meanwhile, it had also become clear that calcium is an ambivalent messenger. Hardly anything important occurs in cells without the participation of the calcium message, but calcium must be controlled with absolute precision. This is an imperative necessity, which becomes unfortunately impaired in a number of disease conditions that transform calcium into a messenger of death.

Dynamic Regulation of the Mitochondrial Proton Gradient during Cytosolic Calcium Elevations

“…Several lines of evidence indicate that the activity of the PMCA could account for the drop in pH associated with [Ca 2+ ] cyt elevations. First, La 3+ , at millimolar concentrations known to inhibit the PMCA ( 53 ), completely inhibited histamine-induced decreases in pH cyto (not shown) and pH mito while enhancing [Ca 2+ ] cyt elevations ( Fig. 5 A ).…”

“…5 C , ii ), consistent with a role for the PMCA in the acid generation. Inhibition of PMCA has also been shown for orthovanadate, with sensitivities ranging from micromolar to millimolar concentrations ( 53 ). We observed little to no inhibition of histamine-induced acidification at micromolar concentrations of orthovanadate, but 1 and 10 m m orthovanadate inhibited both pH cyto and pH mito acidifications by ∼30% (data not shown).…”

Electrocatalytic oxidation of tyrosines shows signal enhancement in label-free protein biosensors

“…2, the electrooxidation current of native BSA catalyzed by Os (bpy) 2 dppz 2+ was 7-fold higher than BSA alone, which resembles the case of free Tyr. However, the second order rate constant between BSA and Os(bpy) 2 39,2012 found to be only 12.0/M/s, which is about 200-fold slower than that with free Tyr (2.0 · 10 3 /M/s). Also, the current from BSA ($3.1 lA) was apparently smaller than that of the latter ($5.5 lA) despite having nearly same number of Tyr in both cases.…”

“…Plasmatransport proteins bind to particular small molecules and transport them to other locations where they are needed (e.g., oxygen is transported by hemoglobin from the lungs to other organs and tissues). Some membrane proteins pump ions across the membrane {e.g., Ca 2+ pump [2]}, while others act as ''receptors'' [3] that bind to signaling molecules on the cell surface and induce biochemical response inside the cell. Such signaling responses within cells often depend on protein modifications, namely post-translational modifications (PTMs) [4][5][6][7][8], in which chemical functional groups (e.g., phosphate, acetate, carbohydrate) are covalently attached to protein amino-acid (AA) residues under the action of enzymes {e.g., signaling can be turned ''ON'' in terms of protein phosphorylation by protein kinases [9], and switched ''OFF'' as dephosphorylation by phosphatases}.…”