Calcium- and calmodulin-dependent inhibition of NMDA receptor currents

Abstract

Calcium ions (Ca²⁺) reduce NMDA receptor currents through several distinct mechanisms. Among these, calmodulin (CaM)-dependent inhibition (CDI) accomplishes rapid, reversible, and incomplete reduction of the NMDA receptor currents in response to elevations in intracellular Ca²⁺. Quantitative and mechanistic descriptions of CDI of NMDA receptor-mediated signals have been marred by variability originating, in part, from differences in the conditions and metrics used to evaluate this process across laboratories. Recent ratiometric approaches to measure the magnitude and kinetics of NMDA receptor CDI have facilitated rapid insights into this phenomenon. Notably, the kinetics and magnitude of NMDA receptor CDI depend on the degree of saturation of its CaM binding sites, which represent the bona fide calcium sensor for this type of inhibition, the kinetics and magnitude of the Ca²⁺ signal, which depends on the biophysical properties of the NMDA receptor or of adjacent Ca²⁺ sources, and on the relative distribution of Ca²⁺ sources and CaM molecules. Given that all these factors vary widely during development, across cell types, and with physiological and pathological states, it is important to understand how NMDA receptor CDI develops and how it contributes to signaling in the central nervous system. Here, we review briefly these recent advances and highlight remaining questions about the structural and kinetic mechanisms of NMDA receptor CDI. Given that pathologies can arise from several sources, including mutations in the NMDA receptor and in CaM, understanding how CaM responds to intracellular Ca²⁺ signals to initiate conformational changes in NMDA receptors, and mapping the structural domains responsible will help to envision novel therapeutic strategies to neuropsychiatric diseases, which presently have limited available treatments.