In conclusion, we provide evidence that IP-HD tightening is crucial for P2X3 channel opening, and based on this mechanism, inhibitors targeting P2X3-specific allosteric modulation at IP-HD were found to have cough-suppressing effects without the side effect of taste dysregulation, as the current P2X3-based cough-suppressant. This evidence concerns the gene P2RX3 and Cough.