The Na⁺/Ca²⁺ exchanger: molecular structure, functional regulation, and mode-selective modulation

The Na⁺/Ca²⁺ exchanger (NCX) is a key regulator of intracellular Ca²⁺ homeostasis, mediating bidirectional ion transport in response to electrochemical gradients. NCX plays essential roles in diverse physiological processes, including cardiac contraction, neuronal signaling, and hormone secretion, while its dysregulation is implicated in a wide range of pathophysiological conditions such as heart failure, ischemia, and neurodegenerative diseases. Recent advances in structural biology, particularly cryo-electron microscopy, have provided detailed insights into the molecular architecture of eukaryotic NCX, revealing the mechanisms underlying ion transport, regulation, and inactivation. These studies have highlighted the functional importance of conserved structural elements, including the α1- and α2-repeats and cytosolic regulatory domains, in governing exchanger activity. In parallel, pharmacological studies have identified a variety of NCX modulators with distinct mode and isoform selectivity. While classical inhibitors predominantly target the reverse mode, emerging compounds-including highly selective inhibitors and novel activators-demonstrate diverse mechanisms of action, often involving allosteric modulation rather than direct interaction with the ion-binding site. This review integrates current knowledge of NCX structure, function, and pharmacology, with a particular focus on the relationship between structural determinants and transport mode selectivity. We also discuss the challenges that have limited the clinical translation of NCX-targeting drugs and outline future perspectives for the rational design of next-generation NCX modulators.