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Potassium channel-interacting proteins (KChlPs) are EF-hand calcium-binding proteins of the recoverin/neuronal calcium sensor 1 family that co-assemble with the pore-forming Kv4 α-subunits and thus control surface trafficking of the voltage-gated potassium channels mediating the neuronal 1A and cardiac Ito currents. Different from the other KChlPs, KChIP4a largely reduces surface expression of the Kv4 channel complexes. Using solution NMR we show that the unique N terminus of KChlP4a forms a 6-turn α-helix that is connected to the highly conserved core of the KChlP protein via a solvent-exposed linker. As identified by chemical shift changes, N-terminal α-helix and core domain of KChlP4a interact with each other through the same hydrophobic surface pocket that is involved in intermolecular interaction between the N-terminal helix of Kv4α and KChIP in Kv4-KChlP complexes. Electro- physiological recordings and biochemical interaction assays of complexes formed by wild-type and mutant Kv4α and KChlP4a proteins suggest that competition of these two helical domains for the surface groove is responsible for the reduced trafficking of Kv4-KChlP4a complexes to the plasma membrane. Surface expression of Kv4 complexes may thus be controlled by an auto- inhibitory domain in the KChIP subunit. [ABSTRACT FROM AUTHOR]

Information processing and storage in the brain rely on AMPA-receptors (AMPARs) and their context-dependent dynamics in synapses and extra-synaptic sites. We found that distribution and dynamics of AMPARs in the plasma membrane are controlled by Noelins, a three-member family of conserved secreted proteins expressed throughout the brain in a cell-type-specific manner. Noelin tetramers tightly assemble with the extracellular domains of AMPARs and interconnect them in a network-like configuration with a variety of secreted and membrane-anchored proteins including Neurexin1, Neuritin1, and Seizure 6-like. Knock out of Noelins1-3 profoundly reduced AMPARs in synapses onto excitatory and inhibitory (inter)neurons, decreased their density and clustering in dendrites, and abolished activity-dependent synaptic plasticity. Our results uncover an endogenous mechanism for extracellular anchoring of AMPARs and establish Noelin-organized networks as versatile determinants of constitutive and context-dependent neurotransmission. [Display omitted] • Noelins1–3 are highly abundant secreted proteins expressed throughout the brain • Noelin tetramers interlink AMPARs with extracellular networks of proteins • Noelins are required for activity-dependent synaptic plasticity • Noelins are "universal" anchors controlling distribution and dynamics of AMPARs Processing and storage of information in the mammalian brain critically rely on AMPA-receptors (AMPARs) and their context-dependent dynamics. Boudkkazi et al. show that distribution and dynamics of AMPARs in the surface membrane are controlled by Noelins, highly conserved secreted proteins that are abundantly expressed throughout the brain in a cell-type-specific manner. [ABSTRACT FROM AUTHOR]