Neuroscience Program, School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA.
Channels (Austin). 2013 Mar-Apr;7(2):126-32. doi: 10.4161/chan.23968. Epub 2013 Mar 1.
NMDA receptors are glutamate-activated, Ca ( 2+) -permeable ion channels with critical roles in synaptic transmission and plasticity. The shape and size of their current is modulated by several kinase/phosphatase systems, and numerous residues located on the receptors' intracellular C-termini are phosphorylated in vivo. To investigate the mechanisms by which phosphorylation may control channel gating, we examined the single-channel behaviors of receptors carrying the S900A or S929A substitution in their GluN2A subunits and thus were rendered resistant to phosphorylation at those sites. We found that the mutations reduced channel open probability primarily by increasing the frequency of desensitized events. The kinetic models we developed revealed complex but similar changes in mechanism for the two mutants, leading to the view that dephosphorylation at either site may cause receptors to activate slower, deactivate faster and desensitize more frequently. This modulatory mechanism is consistent with the proposed roles for these residues in Ca ( 2+) -dependent desensitization and calcineurin-mediated reduction of current during brain development.
NMDA 受体是谷氨酸激活的、Ca(2+)-通透的离子通道，在突触传递和可塑性中具有关键作用。其电流的形状和大小受几种激酶/磷酸酶系统调节，并且位于受体细胞内 C 末端的许多残基在体内被磷酸化。为了研究磷酸化可能控制通道门控的机制，我们研究了在其 GluN2A 亚基中携带 S900A 或 S929A 取代的受体的单通道行为，从而使其对这些位点的磷酸化具有抗性。我们发现，突变主要通过增加脱敏事件的频率来降低通道的开放概率。我们开发的动力学模型揭示了两种突变体在机制上的复杂但相似的变化，导致这样的观点，即两个位点中的任一位点去磷酸化可能导致受体激活更慢、失活更快且脱敏更频繁。这种调节机制与这些残基在 Ca(2+)-依赖性脱敏和脑发育过程中钙调神经磷酸酶介导的电流减少中的作用一致。
