J Gen Physiol. 2026 Nov 2;158(6):e202614039. doi: 10.1085/jgp.202614039. Epub 2026 Aug 27.

ABSTRACT

Most ionotropic neurotransmitter receptors are hetero-oligomers of three to five homologous subunits assembled into membrane-spanning ion channels. Mammalian AMPA-type glutamate receptors (AMPARs), which emerged in animals with centralized nervous systems and now mediate most of the excitatory synaptic signaling in our brain, readily assemble as homotetramers, yet often occur as heterotetramers of two to three different AMPAR subunits. Here, we looked for unifying functional properties of the AMPAR family using molecular phylogenetics, together with electrophysiological and pharmacological characterization of heterologously expressed AMPARs from the three major lineages within bilaterian animals. Our results suggest that the hallmark of AMPAR evolution is selective activation by glutamate, fast kinetics, and the duplication of AMPAR genes independently in new animal lineages, such that most major bilaterian groups have relatively unique complements of AMPAR genes. Moreover, in diverse bilaterians, these novel AMPAR subunits have (1) come to rely on each other for functional expression, resulting in obligate heterotetrameric AMPARs, and (2) sub-functionalized, with various subunits contributing differently to channel activation or ion permeation. Remarkably, this evolution appears to have independently converged on a complement of calcium-sensitive and calcium-insensitive AMPARs in mammals and worms via biophysically similar but genetically different mechanisms.

PMID:42658190 | DOI:10.1085/jgp.202614039