In summary, this study showed that: i) GSP depolarized the pacemaker potentials in ICC; ii) Y25130, a 5-HT3 antagonist, and SB269970, a 5-HT7 antagonist, inhibited GSP‐induced responses; iii) PKC, PKA, and MAPK inhibitors inhibited GSP‐induced responses; iv) GSP increased ITR values in normal and GMD mice; v) GSP elevated the levels of MTL and SP hormones but had no effect on the levels of SS and VIP; vi) SM‐induced ITR increase was related to the increase in the protein expression of c‐kit and the TMEM16A proteins. The gene discussed is PRRT2; the disease is intrahepatic cholangiocarcinoma.