Sigma Receptor and cocaine sensitization

sigma-1受体（Sig-1R）是一种内质网（ER）伴侣蛋白，是一种细胞器间信号调节剂，可能在药物寻找行为中发挥作用。然而，大脑的作用部位和潜在的细胞机制仍未确定。我们发现可卡因暴露触发伏隔核（NAc）中d型K+电流的sig1r依赖性上调，导致神经元活性降低，从而增强行为可卡因反应。结合离体和体外研究，我们证明了这种神经适应是由Sig-1Rs和Kv1.2通道之间持续的蛋白质关联引起的，这种现象与两种蛋白质从细胞内隔室重新分配到质膜有关。总之，动态Sig-1R-Kv1.2复合物代表了一种形成神经元和行为对可卡因反应的机制。Sig-1R结合K+通道的功能后果可能对其他慢性疾病有影响，其中不适应的内在可塑性和Sig-1R参与其中。

The sigma-1 receptor (Sig-1R), an endoplasmic reticulum (ER) chaperone protein, is an interorganelle signaling modulator that potentially plays a role in drug-seeking behaviors. However, the brain site of action and underlying cellular mechanisms remain unidentified. We found that cocaine exposure triggers a Sig-1R-dependent upregulation of D-type K+ current in the nucleus accumbens (NAc) that results in neuronal hypoactivity and thereby enhances behavioral cocaine response. Combining ex vivo and in vitro studies, we demonstrated that this neuroadaptation is caused by a persistent protein-protein association between Sig-1Rs and Kv1.2 channels, a phenomenon that is associated to a redistribution of both proteins from intracellular compartments to the plasma membrane. In conclusion, the dynamic Sig-1R-Kv1.2 complex represents a mechanism that shapes neuronal and behavioral response to cocaine. Functional consequences of Sig-1R binding to K+ channels may have implications for other chronic diseases where maladaptive intrinsic plasticity and Sig-1Rs are engaged.