부산대학교 도서관

Big or high conductance potassium (BK) channels are activated by voltage and intracellular calcium (Ca2+). Phosphatidylinositol 4,5-bisphosphate (PIP2), a ubiquitous modulator of ion channel activity, has been reported to enhance Ca2+-driven gating of BK channels, but a molecular understanding of this interplay or even of the PIP2 regulation of this channel's activity remains elusive. Here, we identify structural determinants in the KDRDD loop (which follows the αA helix in the RCK1 domain) to be responsible for the coupling between Ca2+ and PIP2 in regulating BK channel activity. In the absence of Ca2+, RCK1 structural elements limit channel activation through a decrease in the channel's PIP2 apparent affinity. This inhibitory influence of BK channel activation can be relieved by mutation of residues that (a) connect either the RCK1 Ca2+ coordination site (Asp367 or its flanking basic residues in the KDRDD loop) to the PIP2-interacting residues (Lys392 and Arg393) found in the αB helix or (b) are involved in hydrophobic interactions between the αA and αB helix of the RCK1 domain. In the presence of Ca2+, the RCK1-inhibitory influence of channel-PIP2 interactions and channel activity is relieved by Ca2 + engaging Asp367. Our results demonstrate that, along with Ca2+ and voltage, PIP2 is a third factor critical to the integral control of BK channel activity. [ABSTRACT FROM AUTHOR]