When extracellular osmolarity exceeds intracellular osmolarity,cells initially shrink but then approach the original cell volume by so-called regulatory cell volume increase(RVI).RVI operates under physiological conditions so that impairment of RVI leads to immediate cell cycle arrest and apoptosis.In a cervical cancer cell line,HeLa cells, extracellular hypertonicity induced non-selective cation currents (I currents)which transported mainly Na into cells to induce RVI as assessed with the patch-clamp method. Ion channels mediating these currents were Ca -impermeable and sensitive to flufenamic acid(FFA)and econazole but not to amiloride or ruthenium red.RT-PCR indicated that HeLa cells express transient receptor potential(TRP) C1,C6,M3,M4,M7,M8,V1 and V2 subunits which form non-selective cation channels.From these results, we speculated that TRPM4 may mediate I currents.Indeed,transduction of a dominant-negative TRPM4 subunit significantly inhibited I currents.TRPM4 channels became insensitive to hypertonic stimulus when intracellular Ca was strongly buffered.Thus,extracellular hypertonicity activates TRPM4 channels through intracellular Ca to induce RVI in HeLa cells.These results indicate that intra-uterus or-vaginal application of drugs blocking TRPM4 channels may cause antiproliferative/proapoptotic effects on cervical cancer. Shinshu Med J 62 : 33―44, 2014 (Received for publication August 7,2013;accepted in revised form September 10,2013)