Overview
Neurosteroids reshape NMDA receptor pores, controlling how strongly electrical forces pull sodium and calcium from the extracellular fluid into neurons during activation. Cryo-EM mapping of GluN1a-2B shows that steroid and oxysterol ligands bind to juxtamembrane pockets that bend the M3 helices forming the ion pathway. These structural changes alter pore diameter and hydration, adjusting how easily ions flow through and defining the amplitude of each excitatory pulse (Kang et al., 2025).
Origin and Relationship to Cortisol
Both neurosteroids and cortisol originate from cholesterol via conversion to pregnenolone within mitochondria by CYP11A1. Cortisol is produced in the adrenal cortex and acts through glucocorticoid receptors to increase NMDA and AMPA receptor expression at the genomic level. Neurosteroids are synthesized locally in brain tissue and act at the membrane surface, quickly modulating the ion flow of existing receptors. The two systems complement one another: cortisol increases receptor number, while neurosteroids regulate how easily sodium and calcium are pulled through each receptor opening.
Structural Mechanism
Neurosteroids and oxysterols bind specialized juxtamembrane pockets near the channel gate on GluN2B subunits.
- 24S-hydroxycholesterol stabilizes a fully open conformation where GluN1a and GluN2B helices bend outward, widening the pore and allowing stronger inward flow of sodium and calcium when the receptor opens (Kang et al., 2025).
- EU1622-240 stabilizes a sub-open state that constrains pore dilation and reduces ionic flow while maintaining signaling (Kang et al., 2025).
- Pregnenolone sulfate binds the same region in a dual-ligand configuration, creating variable pore geometries and distinct conductance states (Kang et al., 2025).
Ion Source and Flow
The ions conducted by NMDA receptors are drawn from the extracellular space. When glutamate and glycine activate the receptor, the channel opens and the neuron’s negative interior pulls sodium and calcium inward, while potassium exits. Neurosteroid binding modifies the ease of this electrical pull by reshaping the gate region, changing resistance to ion movement rather than ion availability. This defines how much charge and calcium signaling load each receptor event contributes to the neuron.
Functional Convergence with Stress
Stress elevates cholesterol turnover and pregnenolone synthesis. Cortisol produced through this route increases receptor expression via nuclear signaling. Simultaneously, neurosteroids reshape NMDA receptor pores so that each opening allows ions to be drawn in more readily by the membrane’s electrical gradient. This combined enhancement of receptor number and ion conductance raises total excitatory current and mitochondrial calcium entry, promoting ROS generation and excitotoxic stress within the glutamatergic network.
Summary
Neurosteroids act as structural regulators of NMDA receptor pores, fine-tuning how efficiently sodium and calcium are pulled into neurons by electrical forces during activation. This rapid, local control complements cortisol’s genomic regulation of receptor expression. Together they form a coupled system linking steroid metabolism, ion conductance, and oxidative stress, showing how biochemical state governs the excitatory pressure driving neuronal metabolism and vulnerability.
References
| Title | Authors | Year |
|---|---|---|
| Mechanism of conductance control and neurosteroid binding in NMDA receptors | Kang et al. | 2025 |