Protons are positively charged hydrogen ions (H⁺) and the H⁺ concentration in solution is conventionally represented by its negative log value, or pH. All cells carefully regulate their pH, and pH homeostasis is integral for cell survival, organ function, and organism viability. The cell membrane is impermeable to H⁺ and the passage of H⁺ in and out of the cell occurs through membrane transport processes. Many of these transporters have been identified at the molecular level. The next major challenge in physiology is bridging the gap between molecular and integrative functions, or how processes occurring at the cell level are organized to convey systems functions.

This project is designed to explore a novel mechanism for fast cell-cell communication using protons as a transmitter, and to determine how pH synergizes with oscillatory Ca²⁺ signaling in a live, behaving organism. It has recently been shown (by the PI’s lab and others) that Ca²⁺ waves, intestinal pH oscillations and trans-epithelial proton transport together regulate the timing and execution of a rhythmic behavior in the nematode C. elegans. During this behavior, contraction of the muscles that surround the intestine is triggered through regulated proton extrusion from the intestine itself. This is the first example of protons actively transmitting information between cells. Furthermore, since proton “hopping” across water molecules is not diffusion limited, the rate at which pH can operate as a signaling mechanism is in fact faster than many neurotransmitters. Moreover, since this behavior also represents a genetic, integrative model for studying oscillatory Ca²⁺ signaling and Ca²⁺ wave propagation in non-excitable cells, these recent findings suggest a unique opportunity to study the functional intersection between pH and Ca²⁺ signaling. The investigators will employ during the course of these studies fluorescent biosensors to measure Ca²⁺ and pH in live worms, pharmacologic tools to exert spatial and temporal control over second messenger production, genetic mutants with dysfunction in ion transport processes, and molecular techniques to address structure function relationships in vivo and in vitro. This combination of integrative physiology and molecular genetics is focused on mechanistically addressing the central hypothesis “Ca²⁺ and pH signals are synergistic”.