Figure 7. Simulated voltage responses to triangular current ramp injections, and underlying mechanisms.

(A) Simulated control response to triangular current ramp. (A1) Top. Simplified model calcium handling schematic. For simplicity, only one annulus (shell) is shown, and the rest are represented as the core. Ca²⁺ enters via voltage-gated Ca²⁺ channels (Ca_V) and is removed by the plasma membrane Ca²⁺ ATPase (PMCA) pump. Inside the cell, buffering and the endoplasmic reticulum (ER) are also modeled. The TRPM4 channel is not permeable to Ca²⁺ and senses [Ca²⁺] in a nanodomain (ND). In the control simulation, the nanodomain is contiguous with the cytosol. Bottom trace shows the voltage responses, plotted in the somatic compartment, to a triangular current ramp applied in the soma (shown below). (A2) Ca²⁺ concentration (in nM) in the outermost shell of the somatic compartment. (A3) The nanodomain Ca²⁺ concentration (same as the that of the outer shell in A2 in this case) is negligible when plotted in μM scale. (A4) TRPM4 activation is negligible in control. B. Simulated response to triangular current ramp during simulated application of CCh. (B1) As in A1 except for ligand (magenta dot) binding to the metabotropic acetylcholine receptor (mAChR), triggering Ca²⁺ influx into a nanodomain linked to the TRPM4 channel. The voltage trace shows that the center of mass of firing is shifted to later times. (B2) Ca²⁺ concentration (in nM) in the outermost shell of the somatic compartment. (B3) In contrast to control, the addition of a nanodomain with privileged Ca²⁺ access allows micromolar concentrations to be reached and sensed by TRPM4 channels. (B4) In contrast to control, TRPM4 is now activated during the ramp. Vertical dashed red line shows the peak of the current ramp.