Scan: A Novel Small-Conductance Ca2+-Activated Non-Selective Cation Channel Encoded by TMEM16F

Abstract

Raising internal calcium level causes channel opening to regulate a wide range of cellular functions including neuronal signalling, muscle contraction and excitation-secretion coupling. Named after their ion selectivity, Ca2+-activated K+ channels such as the BK and SK channels with big and small single channel conductance respectively, Ca2+-activated Cl- channels (CaCC), and Ca2+-activated non-selective cation channels (CAN) respond to Ca2+ entry through ligand-gated or voltage-gated ion channels, or Ca2+ release from internal stores. Recently, we and others identified two of the ten members of the mammalian TMEM16 family, TMEM16A and TMEM16B, as CaCC. Here we show that, surprisingly, expression of another family member, TMEM16F, in Axolotloocytes yielded Ca2+-activated non-selective cation channels with novel properties. In contrast to the CAN channels that permeate mainly monovalent cations and show relatively little voltage sensitivity, the TMEM16F-induced channels permeate divalent cations as well and exhibit synergistic gating by Ca2+ and voltage - the higher the internal Ca2+ level, the less depolarization necessary for channel activation. Moreover, the sub picosiemens single channel conductance of the Ca2+-permeable TMEM16F channel is much smaller than the single channel conductance of the CAN channels whose discovery was ushered in by the advent of single channel recording three decades ago. This surprise finding of the novel SCAN channel (small-conductance Ca2+-activated non-selective cation channel) generated by TMEM16F, which is broadly expressed in many different cell types, will enable genetic studies of its physiological functions as exemplified by recent studies of Tmem16a mutant mice, and facilitate development of specific channel modulators of potential therapeutic applications.