# Calcium Signaling Is a Universal Carbon Source Signal Transducer and Effects an Ionic Memory of Past Carbon Sources

## TL;DR

Cells use calcium signaling to adapt to different carbon sources and remember past ones, influencing gene expression.

## Contribution

Discovery of a universal calcium signaling mechanism that transmits carbon source information and retains an ionic memory of past sources.

## Key findings

- Glycolysis metabolites G1P and G6P activate calcium signaling to regulate gene expression based on carbon sources.
- Calcium signaling has an ionic memory of past carbon sources, affecting downstream gene expression like ZWF1.
- The signaling pathway bifurcates, with calcineurin and Cmk1 regulating different genes depending on carbon source.

## Abstract

Glucose is the preferred carbon source for most cells. However, cells may encounter other carbon sources that can be utilized. How cells match their metabolic gene expression to their carbon source, beyond a general glucose repressive system (catabolite repression), remains little understood. By studying the effect of up to seven different carbon sources on Snf1 phosphorylation and on the expression of downstream regulated genes, we searched for the mechanism that identifies carbon sources. We found that the glycolysis metabolites glucose-6-phosphate (G6P) and glucose-1-phosphate (G1P) play a central role in the adaptation of gene expression to different carbon sources. The ratio of G1P and G6P activates analogue calcium signaling via the proton-exporter Pma1 to regulate downstream genes. The signaling pathway bifurcates with calcineurin-reducing ADH2 (alcohol dehydrogenase) expression and with Cmk1-increasing ZWF1 (glucose-6-phosphate dehydrogenase) expression. Furthermore, calcium signaling is not only regulated by the present carbon source; it is also regulated by past carbon sources. We were able to manipulate this ionic memory mechanism to obtain high expression of ZWF1 in media containing galactose. Our findings provide a universal mechanism by which cells respond to all carbon sources.