CAX1 beyond calcium transport: evidence for a transport-independent regulatory module in plants

Plant cation/H+ exchanger 1 (CAX1) is a vacuolar Ca²⁺/H⁺ antiporter that plays a central role in calcium homeostasis. The initial 36 residues of CAX1 make up the amino-terminal regulatory region (NRR), this defining feature mediates autoinhibition and serves as a target for phosphorylation and protein-protein interactions. While CAX1 has been viewed as a transporter, recent genetic studies suggest a broader functional role. Loss of CAX1 enhances tolerance to anoxia and submergence stress, while synthetic biology reveals that transport-deficient amino-terminal modules of CAX1 influence stress responses. Notably, a dominant-negative amino-terminal construct phenocopies cax1 loss-of-function mutants, whereas a transport-deficient amino-terminal module lacking the autoinhibitory region restores anoxia sensitivity in a cax1 background. These observations are difficult to explain through altered calcium transport alone. In this review, we summarize current understanding of CAX1 structure, regulation, and physiological function and evaluate evidence supporting transport-independent activities of the amino terminus. We propose that the amino-terminal architecture of CAX1 could function as a control module that integrates environmental and cellular cues to influence stress responses. This framework expands the functional scope of CAX1 beyond ion exchange and might suggest that membrane transport proteins contribute directly to signaling networks.