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. 2018 Nov 5;38(2):e99894. doi: 10.15252/embj.201899894

Figure 6. Influence of rolling on single‐receptor gating kinetics.

Figure 6

  1. Representative recordings of patches containing one single wild‐type (WT) or GluN1‐E698C/GluN2B‐L795C receptor. The bottom trace is an expanded view. C, closed channel; O, open channel.
  2. Single‐channel properties (equilibrium channel open probability, mean open time, mean closed time) of the WT and super‐active GluN1‐E698C/GluN2B‐L795C receptors. Mean and n values are given in Appendix Table S4. *P < 0.05, two‐tailed Student's t‐test, unpaired. Error bars, SEM.
  3. Closed (left) and open (right) time histograms for WT (black) or super‐active GluN1‐E698C/GluN2B‐L795C (red) receptors. Closed time histograms were best fit with five exponentials, whereas open time histograms were best fit with two exponentials (see Materials and Methods and Appendix Fig S8). Smooth lines are associated exponential fits.
  4. Kinetic schemes and equilibrium constants for WT (upper panel) or super‐active GluN1‐E698C/GluN2B‐L795C (lower panels) receptors. Records were analyzed at equilibrium. Ligand‐binding steps are shown in gray. Note that for simplicity, long‐lived desensitized steps are not shown. *P < 0.05 relative to WT GluN1/GluN2B (two‐tailed Student's t‐test, unpaired).
  5. Proposed mechanism for the conformational switch in full‐length tetrameric GluN1/GluN2B receptor: Inter‐dimer rolling in the ABD layer is coupled to entry of the NTD layer in its active state. The positive allosteric modulator spermine, which binds the interface between GluN1 and GluN2B NTD lower lobes, enhances receptor activity by stabilizing the NTD compact form and therefore rolling. Conversely, the negative allosteric modulators zinc and ifenprodil inhibit receptor activity by stabilizing an expanded form of the NTDs (lower lobes further apart) thus preventing rolling. The rolling motion facilitates pore opening by acting on the ABD‐TMD connecting linkers.