Activation Mechanisms Underlying Influx-Operated Calcium Entry of TRPP Channels

Abstract

TRPP channels are permeable to Ca2+, and are also regulated by Ca2+. For instance, PKD2L1 (also known as TRPP3) channel can respond to the rapid increase of extracellular calcium, resulting in an influx-operated Ca2+ entry (ICE) (Hu et al. 2015 Cell Reports). However, the molecular mechanism of ICE activation has not been elucidated. In this study, we show that both Ca2+ and the outer pore play dual roles: Ca2+ can act as both charge carrier and activation ligand for channels; meanwhile, the channel pore regions can act as both the selective filter and also the activation gate. The affinity of Ca2+ in the outer pore region is highly correlated with the activation of ICE. The negatively charged residues prefer Ca2+ over Na+ assuring channel activation. Thus, less charged residues or more extracellular Na+ downregulate ICE. Moreover, the actual ion-binding affinity (irrelevant of selectivity here) is highly regulated by other sites within the outer pore. Such active mechanism of Ca2+ and outer pore in activation may also underlie other ion channels.