McGee Thomas P, Bats Cecile, Farrant Mark, Cull-Candy Stuart G
Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London WC1E 6BT, United Kingdom.
Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London WC1E 6BT, United Kingdom
J Neurosci. 2025 May 7;45(19):e1930242025. doi: 10.1523/JNEUROSCI.1930-24.2025.
Calcium-permeable AMPA-type glutamate receptors (CP-AMPARs) contribute to excitatory synaptic transmission and play pivotal roles in normal and detrimental forms of plasticity. Most AMPARs are associated with auxiliary subunits. Transmembrane AMPAR regulatory proteins (TARPs), the prototypical auxiliary subunits, enhance current through CP-AMPAR channels by increasing single-channel conductance and relieving the characteristic voltage-dependent block by endogenous intracellular polyamines, such as spermine. In contrast, the atypical auxiliary subunit GSG1L negatively regulates CP-AMPARs, suppressing current flow by promoting polyamine block and reducing channel conductance. Here, we investigated the role of polyamines in these opposing effects. We show that, in the absence of auxiliary subunits, intracellular spermine decreases CP-AMPAR single-channel conductance. This effect is prevented by the presence of TARPs but enhanced by the presence of GSG1L. Unexpectedly, intracellular spermine is necessary for both GSG1L's attenuation of CP-AMPAR channel conductance and its characteristic slowing of recovery from desensitization. These various effects are determined by specific residues within the channel's selectivity filter and within GSG1L's C-tail. Together, our findings reveal that intracellular polyamines play an essential role in GSG1L's unique ability to negatively regulate many of the key properties of CP-AMPARs.
钙通透型AMPA受体（CP-AMPARs）参与兴奋性突触传递，并在正常和有害形式的可塑性中发挥关键作用。大多数AMPA受体与辅助亚基相关联。跨膜AMPA调节蛋白（TARPs）作为典型的辅助亚基，通过增加单通道电导并解除内源性细胞内多胺（如精胺）引起的特征性电压依赖性阻滞，来增强通过CP-AMPAR通道的电流。相比之下，非典型辅助亚基GSG1L对CP-AMPARs起负调节作用，通过促进多胺阻滞和降低通道电导来抑制电流流动。在此，我们研究了多胺在这些相反作用中的作用。我们发现，在没有辅助亚基的情况下，细胞内精胺会降低CP-AMPAR单通道电导。TARPs的存在可防止这种效应，但GSG1L的存在会增强这种效应。出乎意料的是，细胞内精胺对于GSG1L减弱CP-AMPAR通道电导及其从脱敏状态恢复的特征性减慢都是必需的。这些不同的效应由通道选择性过滤器内和GSG1L C末端的特定残基决定。总之，我们的研究结果表明，细胞内多胺在GSG1L负调节CP-AMPARs许多关键特性的独特能力中起着至关重要的作用。
