Cornichons: Evolution, AMPA receptor modulation, and emerging roles beyond the nervous system

• AMPA receptors are widely distributed in the central nervous system and carry out the fast-excitatory transmission in response to glutamate release. • Cornichons, a set of auxiliary proteins, were first discovered in lower organisms, and in mammals, they associate along with TARPs at hippocampal AMPARs, suggesting an interplay • Physical association of CNIH-2 and CNIH-3 with the AMPARs extensively modulates their gating properties in a subunit dependent manner by slowing deactivation and reducing desensitization. • Recent structures of cornichons in complex with homomeric AMPA receptors and heteromeric AMPA receptor complexes purified from native brain tissue reveal molecular interactions between the two proteins. Cornichons are auxiliary proteins that regulate the functions of AMPA receptors (AMPARs), which mediate fast excitatory transmission in the central nervous system. Initially discovered in lower organisms, cornichons have since been found across various species, including mammals and plants, indicating their conserved and broader roles beyond the nervous system. In mammals, cornichons, particularly CNIH2 and CNIH3, modulate the trafficking, gating, and biophysical properties of AMPARs, often working alongside other auxiliary proteins such as TARPs. Recent structural studies have provided detailed insights into the topology of cornichons, revealing their integration into AMPAR complexes and highlighting their critical role in slowing AMPAR deactivation and desensitization. Their functional impact on excitatory synaptic transmission is subunit-specific and includes the modulation of conductance and ligand affinity. Beyond their role in the central nervous system, cornichons are implicated in intracellular trafficking processes, acting as cargo receptors for various membrane proteins. This review synthesizes current knowledge on cornichon proteins, from their evolutionary origins and structural properties to their roles in AMPAR regulation and cargo transport. The emerging understanding of cornichons in non-neuronal systems and their potential involvement in neurological diseases opens new avenues for research with potential therapeutic applications.