Channel Gating

Large conductance, voltageand Ca 2 -activated K (BK Ca ) channels regulate blood vessel tone, synaptic transmission, and hearing owing to dual activation by membrane depolarization and intracellular Ca 2 . Similar to an archeon Ca 2 -activated K channel, MthK, each of four subunits of BK Ca may contain two cytosolic RCK domains and eight of which may form a gating ring. The structure of the MthK channel suggests that the RCK domains reorient with one another upon Ca 2 binding to change the gating ring conformation and open the activation gate. Here we report that the conformational changes of the NH 2 terminus of RCK1 (AC region) modulate BK Ca gating. Such modulation depends on Ca 2 occupancy and activation states, but is not directly related to the Ca 2 binding sites. These results demonstrate that AC region is important in the allosteric coupling between Ca 2 binding and channel opening. Thus, the conformational changes of the AC region within each RCK domain is likely to be an important step in addition to the reorientation of RCK domains leading to the opening of the BK Ca activation gate. Our observations are consistent with a mechanism for Ca 2 -dependent activation of BK Ca channels such that the AC region inhibits channel activation when the channel is at the closed state in the absence of Ca 2 ; Ca 2