The sigma‐1 receptor modulates NMDA receptor synaptic transmission and plasticity via SK channels in rat hippocampus

Abstract

The sigma receptor (σR), once considered a subtype of the opioid receptor, is now described as a distinct pharmacological entity. Modulation of N‐methyl‐d‐aspartate receptor (NMDAR) functions by σR‐1 ligands is well documented; however, its mechanism is not fully understood. Using patch‐clamp whole‐cell recordings in CA1 pyramidal cells of rat hippocampus and (+)pentazocine, a high‐affinity σR‐1 agonist, we found that σR‐1 activation potentiates NMDAR responses and long‐term potentiation (LTP) by preventing a small conductance Ca²⁺‐activated K⁺ current (SK channels), known to shunt NMDAR responses, to open. Therefore, the block of SK channels and the resulting increased Ca²⁺ influx through the NMDAR enhances NMDAR responses and LTP. These results emphasize the importance of the σR‐1 as postsynaptic regulator of synaptic transmission.