Biophysical models reveal the relative importance of transporter proteins and impermeant anions in chloride homeostasis

Fast synaptic inhibition in the nervous system depends on the transmembrane flux of Cl- ions based on the neuronal Cl- driving force. Established theories regarding the determinants of Cl- driving force have recently been questioned. Here we present biophysical models of Cl- homeostasis using the pump-leak model. Using numerical and novel analytic solutions, we demonstrate that the Na+/K+-ATPase, ion conductances, impermeant anions, electrodiffusion, water fluxes and cation-chloride cotransporters (CCCs) play roles in setting the Cl- driving force. Our models, together with experimental validation, show that while impermeant anions can contribute to setting [Cl-]i in neurons, they have a negligible effect on the driving force for Cl- locally and cell-wide. In contrast, we demonstrate that CCCs are well-suited for modulating Cl- driving force and hence inhibitory signalling in neurons. Our findings reconcile recent experimental findings and provide a framework for understanding the inter...神经系统中的快速突触抑制，依赖于基于神经元氯离子(Cl⁻)驱动力的氯离子跨膜通量。此前关于氯离子驱动力决定因素的主流理论，近来受到了学界质疑。本研究采用泵漏模型(pump-leak model)，构建了氯离子稳态的生物物理模型。通过数值解法与全新解析解法的分析，本研究证实：钠钾腺苷三磷酸酶(Na+/K+-ATPase)、离子电导、不可通透阴离子、电扩散、水通量以及阳离子-氯离子协同转运体(CCCs)，均参与调控氯离子驱动力的形成。本研究模型结合实验验证结果表明：尽管不可通透阴离子可参与调控神经元内的细胞内氯离子([Cl⁻]i)浓度，但它们在局部及全细胞层面对氯离子驱动力的影响均微乎其微。与之相反，本研究证实阳离子-氯离子协同转运体(CCCs)非常适于调控神经元的氯离子驱动力，进而调控神经元的抑制性信号传导。本研究的发现调和了近期的多项实验结论，并为理解[...]提供了理论框架。