Summary: A new structural biology study resolves a decades-old question in neuroscience: how brain receptors distinguish calcium from magnesium to enable learning and memory. Using single-particle cryo-electron microscopy (cryo-EM), high-performance computing, and electrophysiology validation, researchers captured more than 50,000 microscopic movies of the NMDA receptor (NMDAR) channel to reveal how a molecular filter selectively permits calcium while blocking magnesium.
High-resolution structural maps show that a specialized constriction inside the NMDAR pore—the Asn cage—forces calcium ions to shed part of their surrounding water shell (partial dehydration) to pass through. Magnesium, by contrast, retains a tightly bound hydration shell and cannot pass the narrow filter, so it acts as a plug that controls synaptic signaling and plasticity.
Key Facts
- The chemical challenge: Calcium (Ca2+) and magnesium (Mg2+) are adjacent on the periodic table and carry the same charge, so discriminating between them is a structural challenge for ion channels.
- Dehydration matters: Magnesium binds water more tightly than calcium, making it far harder to strip away its hydration shell before entering a tight pore.
- The Asn cage filter: The selectivity filter inside the NMDAR, centered on conserved asparagine residues, functions like a molecular sieve. Dehydrated calcium can fit through; hydrated magnesium is too bulky and becomes a blocker.
- Large-scale imaging: Because water molecules are dynamic, the team collected millions of raw cryo-EM images and assembled more than 50,000 high-resolution movies to resolve transient ion and water positions.
- Clinical relevance: The Asn cage region is sensitive to spontaneous mutations implicated in GRIN disorders—severe neurodevelopmental conditions that produce profound cognitive and motor impairments and often refractory seizures.
Source: CSHL
How memory formation depends on ion selectivity.
At its core, learning involves precisely timed chemical and electrical events at synapses. NMDARs are central players: at rest, magnesium blocks the receptor pore and prevents calcium entry. When a strong synaptic signal depolarizes the postsynaptic membrane, magnesium is relieved and calcium flows in. That calcium influx triggers downstream signaling that stabilizes synaptic changes—one molecular basis of memory.
Although neuroscientists long understood the functional roles of calcium and magnesium at NMDARs, the exact structural mechanism that lets the receptor distinguish these two similar divalent cations was unresolved. The new study from Cold Spring Harbor Laboratory (CSHL), led by Professor Hiro Furukawa with postdoctoral researcher Rubin Steigerwald and colleagues, provides a detailed answer by directly visualizing ions, water, and protein atoms during permeation and block.
The key difference is hydration energy: magnesium tightly coordinates water molecules and is reluctant to lose them, while calcium does so more readily. Using single-particle cryo-EM, the researchers focused on the narrow constriction formed by conserved asparagine residues—the Asn cage—inside the channel pore. The structural reconstructions reveal multiple calcium binding positions that reflect partial dehydration as calcium squeezes through the filter. Magnesium, however, binds outside the selectivity filter through an organized water network and remains hydrated, effectively plugging the channel.
Resolving these subtle differences required exceptional resolution because water molecules and ion coordination are highly dynamic. The team therefore collected an enormous dataset—millions of images consolidated into over 50,000 cryo-EM movies—and combined those maps with electrophysiological recordings to verify that the observed positions correspond to functional ion transit and block.
Beyond the fundamental insight into ion selectivity, the findings have immediate biomedical significance. Mutations that alter the Asn cage geometry are linked to a group of conditions called GRIN disorders. These mutations can deform the filter, change ion permeability or block properties, and thereby disrupt the neural signaling required for normal development. By producing a clear structural “blueprint” of the filter in action, the study provides a foundation for structure-guided drug design aimed at correcting dysfunctional channels in affected patients.
Key Questions Answered:
A: NMDA receptors gate the molecular events that underlie synaptic plasticity. Magnesium provides a voltage-dependent block that prevents random calcium influx. When a meaningful depolarization lifts that block, calcium enters and triggers biochemical changes that stabilize synapses. If the receptor could not distinguish calcium from magnesium, the timing and regulation of these signaling events would fail, disrupting memory formation.
A: Ions in solution are surrounded by shells of water molecules. To pass through an extremely narrow filter such as the Asn cage, an ion often must shed some of those waters. Calcium can partially dehydrate to fit into the constriction; magnesium’s water shell is held more tightly, preventing that step and leaving it too large to pass.
A: Many GRIN disorder mutations map to the Asn cage or nearby regions that control ion binding and permeation. By revealing the precise geometry and chemistry of calcium permeation and magnesium block, the structural blueprint can guide targeted therapies—small molecules or biologics—that stabilize the filter or compensate for mutation-induced changes.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- The full journal paper was reviewed.
- Additional context was added by staff.
About this learning and memory research news
Author: Samuel Diamond
Source: CSHL
Contact: Samuel Diamond – CSHL
Image: Image credit: Neuroscience News
Original Research: Open access. “Molecular mechanism of calcium permeability and magnesium block in NMDA receptors” by Ruben Steigerwald, Max Epstein, Tsung-Han Chou, Noriko Simorowski & Hiro Furukawa. Published in Nature Neuroscience. DOI and journal information available in the paper.
Abstract
Molecular mechanism of calcium permeability and magnesium block in NMDA receptors
Hebbian neuroplasticity, a cellular substrate for learning and memory, depends on coincident detection of presynaptic neurotransmitter release and postsynaptic Ca2+ influx during depolarization. This process is mediated by N-methyl-D-aspartate-type glutamate receptors, which bind glutamate and glycine and permit Ca2+ influx when Mg2+ channel block is relieved during membrane depolarization.
The structural basis for Ca2+ permeability and Mg2+ blockade in these receptors has not been fully understood. Using single-particle cryo-electron microscopy, the study demonstrates that Ca2+ permeation through the narrow selectivity filter involves partial dehydration, as seen in multiple Ca2+ binding sites within the constriction. In contrast, Mg2+ binds outside the selectivity filter via a water network and remains hydrated, thereby acting as a channel blocker. Lipids surrounding the selectivity filter influence Mg2+ binding stability in a voltage-dependent manner. The work details the transmembrane chemistry essential for initiating neuroplasticity.