Proteins of Tmem16 family are the candidate subunits for Ca2+-activated Cl- channels (CaCC). We show that CaCC in nociceptors is activated by the release of Ca2+ from the IP3-sensitive intracellular stores in response to bradykinin(BK) or proteases (through PAR-2 receptors). Interestingly, while in the majority of rat small DRG neurons CaCC was induced by Ca2+ release from the stores, only in 12/58 neurons CaCC was activated by the Ca2+ influx through the voltage-gated Ca2+ channels. Chelating intracellular Ca2+ with the slow Ca2+ buffer EGTA did not affect CaCC activation by PAR2 while BAPTA abolished such activation suggesting a close proximity of the Ca2+ release sites and CaCC. Acute treatment of rat DRG neurons with lipid raft disrupting agent methyl-beta-cyclodextrin partially restored coupling of CaCC to VGCC but disrupted coupling with the intracellular stores. Thus, after the methyl-beta-cyclodextrin treatment activation of VGCC by voltage pulse CaCC currents in majority of neurons while BK and PAR2-AP failed to induce measurable CaCC in the majority of tested neurons. Membrane fractionation demonstrated that in DRG TMEM16A can be co-purified with lipid raft marker caveolin.