Functional interactions of ion channels with the actin cytoskeleton: does coupling to dynamic actin regulate NMDA...

Synapses are enriched in the cytoskeletal protein actin, which determines the shape of the pre- and postsynaptic compartments, organizes the neurotransmitter release machinery, and provides a framework for trafficking of components. In the postsynaptic compartment, interactions with actin or its associated proteins are also critical for the localization and activity of synaptic neurotransmitter receptors and ion channels. Actin binding proteins, including spectrin and α-actinin, serve as molecular linkages between the actin cytoskeleton and a diverse collection of receptors, including the NMDA receptor (NMDAR) and voltage-gated Na⁺ channels. The actin cytoskeleton can regulate neurotransmitter receptors and ion channels by controlling their trafficking and localization at the synapse and by directly gating receptor channel opening. We highlight evidence that synaptic actin couples physically and functionally to the NMDAR and supports its activity. The molecular mechanisms by which actin regulates NMDARs are only just emerging, and recent advancements in light and electron microscopy-based imaging techniques should aide in elucidating these mechanisms.