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.