Large-Pore Channels at the Maternal-Fetal Interface: Progress and Open Research Avenues

The maternal-fetal interface functions as an integrated physiological unit whose homeostatic balance determines pregnancy success. Large-pore channels, composed of connexins (Cxs), pannexins (Panxs), calcium homeostasis modulators (CALHMs) and leucine-rich repeat-containing 8 (LRRC8) proteins, mediate direct intercellular communication, autocrine and paracrine release of ATP and other signaling molecules, and scaffold-based signal integration across this interface. In this review, we synthesize current knowledge on large-pore channel expression and their physiological and pathophysiological roles at the maternal-fetal interface, applying an explicit evidence-classification framework to distinguish established functions from emerging findings. We first map the large-pore channel repertoire of each cellular compartment-syncytiotrophoblast, cytotrophoblast, extravillous trophoblast, villous endothelium and decidual stroma-revealing that each compartment expresses a distinct combination of family members, with varying levels of evidence and gestational stage-dependent dynamics. We then analyze the three principal modes of large-pore channel operation in placental physiology: gap-junctional communication driving syncytialization, channel-mediated ATP release enabling paracrine purinergic signaling, and channel-independent scaffolding functions that integrate mechanical and biochemical signals. Next, we examine how each channel family becomes dysregulated in placental-related diseases. We conclude by outlining a targeted research roadmap with clear priorities: the most urgent need is protein-level validation of CALHM and LRRC8 expression in primary trophoblasts, followed by elucidation of gating mechanisms and testing for crosstalk among channel families. By providing both conceptual synthesis and practical guidance, this review aims to accelerate mechanistic understanding and therapeutic development targeting large-pore channels for pregnancy complications that currently lack mechanism-based treatments.