Abstract

Connexin-43 (Cx43) is the most abundantly expressed member of the connexin family and has long been regarded chiefly as the building block of gap junction channels that couple the cytoplasm of neighbouring cells. This account is correct but incomplete. Work over the past two decades has shown that Cx43 carries out several functions that do not require intercellular channel formation, and some that do not require a channel at all. Its long cytoplasmic C-terminal tail serves as a signalling and scaffolding platform, binding cytoskeletal and regulatory proteins and influencing cell migration, adhesion, proliferation and gene transcription. Internal translation of GJA1 yields truncated isoforms, notably GJA1-20k and GJA1-11k, which traffic to mitochondria and the nucleus and hold distinct functions of their own. Undocked hemichannels permit the release of ATP, glutamate and prostaglandin E2, supporting bone mechanotransduction under physiological conditions but promoting inflammation and tissue injury in disease. The present review gathers the available evidence on these channel-independent, or non-canonical, activities of Cx43 and arranges it by molecular mechanism and by organ system, covering heart, brain, bone, kidney, skin and tumours. Therapeutic implications are also considered, the aim being not to silence Cx43 entirely but to regulate a particular pool, domain or isoform selectively while preserving its channel functions.

Keywords: Connexin-43, Gap junction, Hemichannel, C-terminal tail, GJA1-20k, Mitochondria, Non-canonical function, Tissue homeostasis