Polyamine-mediated channel block of ionotropic glutamate receptors and its regulation by auxiliary proteins.

Most excitatory neurotransmission in the mammalian brain is mediated by a family of plasma membrane-bound signaling proteins called ionotropic glutamate receptors (iGluRs). iGluRs assemble at central synapses as tetramers, forming a central ion-channel pore whose primary function is to rapidly transport Na+ and Ca2+ in response to binding the neurotransmitter l-glutamic acid. The pore of iGluRs is also accessible to bulkier cytoplasmic cations, such as the polyamines spermine, spermidine, and putrescine, which are drawn into the permeation pathway, but get stuck and block the movement of other ions. The degree of this polyamine-mediated channel block is highly regulated by processes that control the free cytoplasmic polyamine concentration, the membrane potential, or the iGluR subunit composition. Recently, an additional regulation by auxiliary proteins, most notably transmembrane AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor regulatory proteins (TARPs), cornichons, and neuropilin and tolloid-like proteins (NETOs), has been identified. Here, I review what we have learned of polyamine block of iGluRs and its regulation by auxiliary subunits. TARPs, cornichons, and NETOs attenuate the channel block by enabling polyamines to exit the pore. As a result, polyamine permeation occurs at more negative and physiologically relevant membrane potentials. The structural basis for enhanced polyamine transport remains unresolved, although alterations in both channel architecture and charge-screening mechanisms have been proposed. That auxiliary subunits can attenuate the polyamine block reveals an unappreciated impact of polyamine permeation in shaping the signaling properties of neuronal AMPA- and kainate-type iGluRs. Moreover, enhanced polyamine transport through iGluRs may have a role in regulating cellular polyamine levels.