The transmembrane channel-like (TMC) protein family consists of 8 members and is relevant for human diseases like hearing loss, papillomavirus infection, epidermodysplasia verruciformis, and cancer. There is a considerable sequence and possibly structural overlap between TMC and anoctamin (TMEM16) proteins, which have been identified recently as Ca²⁺ activated Cl^- channels, while the function of TMC proteins remains obscure. The non-neuronal TMC4 - TMC8 were unable to reproducibly generate ion currents when overexpressed in HEK293 cells, and were detected only in intracellular compartments. Nevertheless, TMC proteins, particularly TMC8, inhibited Ca²⁺ - dependent activation of volume regulated Cl^- currents (I_Cl,swell). TMC8 also inhibited activation of Ca²⁺ dependent anoctamin 1 Cl^- channels, probably by interfering with intracellular Ca²⁺ signaling. TMC8 is known to facilitate uptake of cytosolic zinc into the endoplasmic reticulum by the zinc transporter ZnT-1. Zinc activated a 5-nitro-2-(3-phenylpropylamino)-benzoic acid (NPPB) sensitive Cl^- current, which was not further activated by cell swelling. Based on the present data we propose that zinc i) is a novel intracellular second messenger, ii) controls cytosolic Ca²⁺ signaling, and iii) activates I_Cl,swell.