NMDA Receptor Regulation by Calmodulin and α-Actinin-1

N-methyl-D-aspartate (NMDA) receptors (NMDARs) are Ca2+-permeable ionotropic glutamate receptors in the brain that have critical roles in learning, memory, neural development, and synaptic plasticity. NMDARs are heterotetrameric Ca2+ channels, which open upon binding to the neurotransmitters, glutamate and glycine. Channel opening causes Ca2+ influx that activates a range of Ca2+-dependent cellular processes, including activation of Ca2+-dependent enzymes, which mediates various forms of synaptic plasticity. Prolonged channel opening elevates the intracellular Ca2+ level to a cytotoxic concentration. To maintain Ca2+ homeostasis, NMDAR channel activity is finely regulated by α-actinin (ACTN), which promotes channel opening by reducing the closed time, and by calmodulin (CaM), which promotes Ca2+-dependent channel desensitization (CDD). Defects in the regulation of NMDAR function are associated with a spectrum of neurological diseases. In this review, we integrate cryo-EM structures of NMDARs, NMR structures of the NMDAR cytosolic C0 domain of the GluN1 and GluN2A subunits bound to Ca2+-bound CaM (Ca2+-CaM), and various structures of α-actinin-1 (ACTN1) to construct structural models of NMDAR in the open channel state bound to Ca2+-free ACTN1 and the agonist-bound, desensitized channel state bound to Ca2+-CaM. These structural models provide insights into the Ca2+-dependent conformational changes that promote CDD.