Fig. 3: Conformational changes at the transmembrane region upon channel activation.

a, Superposition of the hTRPM4 structures in the open and closed states with the front subunits (open in blue and closed in wheat) and the neighboring S1–S4 domains (open in green and closed in wheat) highlighted in color. b, Overview of conformational changes at the pore domain and its neighboring S1–S4 (labeled with single quotation marks) between open and closed TRPM4. Red arrows mark the major movements from closed to open state. Key residues for TRPM4 activation are colored in cyan and yellow for the open and closed states, respectively. The conformational changes at the transmembrane region are visualized in Supplementary Video 2. c, Zoomed-in view of the Ca²⁺-induced local conformational change within the S1–S4 domain. d, Zoomed-in view of the coupled movement from the S1–S4 domain to the neighboring pore domain upon channel activation. The red arrow marks the upward swing of the joint region between the S4–S5 linker and S5 that leads to the opening of the pore. e, Functional effect of substitutions of the residues important for TRPM4 activation. Currents were recorded at +100 mV in inside-out patches with 300 μM Ca²⁺ and 10 μM PtdIns(4,5)P₂ diC8 in the bath. Bars represent the mean ± s.d. of n = 5 independent replicates (shown as dots). P values were calculated using a two-sided Student’s t-test. **P < 0.01. f, Structural comparison of the TRPM4 ion conduction pore at various states: apo closed (wheat), Ca²⁺-bound putative desensitized (green), Ca²⁺-PtdIns(4,5)P₂-bound open (blue) and ATP-inhibited (pink). Gating residues I1040 and S1044 are show in stick representation. The front and back subunits were removed for clarity. g, Pore radius along the central axis in the different TRPM4 states.

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