Mechanistic details of BK channel inhibition by the intermediate conductance, Ca2+-activated K channel.
Salivary gland acinar cells have two types of Ca(2+)-activated K channels required for fluid secretion: the intermediate conductance (IK1) channel and the large conductance (BK) channel. Activation of IK1 inhibits BK channels including in small, cell-free, excised membrane patches. As a first step toward understanding the mechanism underlying this interaction, we examined its voltage sensitivity. We found that the IK1-induced inhibition of BK channels was only weakly voltage dependent and not accompanied by alteration in BK gating kinetics. These actions of IK1 on BK channels are not consistent with a mechanism whereby activation of IK1 causes a shift of the BK channel's voltage dependence as occurs for many BK modulatory processes. In a search for other clues about the interaction mechanism, we noted that the N-terminus of the IK1 channel shares some chemical features with the N-terminal regions of two BK subunits known to inhibit BK activity by blocking the cytoplasmic end of the BK pore. Thus, we tested the idea that the N-terminus of IK1 channels may act similarly. We found that a peptide derived from the N-terminal region of the IK1 protein blocked BK channels. Significantly, we also found that the activation of IK1 channels competed with block by the N-terminus peptide. Thus, the activation of IK1 channels inhibits BK channels by a mechanism that involves block of the cytoplasmic pore, not an alteration in the voltage dependence of BK gating. The mediator of this cytoplasmic pore block may be the IK1 N-terminus.
Thompson
Jill
J
Department of Pharmacology and Physiology and the Center for Oral Biology, University of Rochester Medical Center, Rochester, NY 14642, USA.
Begenisich
Ted
T
D000818:Animals; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology*; D007700:Kinetics; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000037:antagonists & inhibitors*; D051379:Mice; D010455:Peptides / Q000378:metabolism* / Q000494:pharmacology; D024681:Potassium Channels, Calcium-Activated / Q000378:metabolism*; D017434:Protein Structure, Tertiary / Q000502:physiology; D012469:Salivary Glands / Q000378:metabolism*
D051036:Large-Conductance Calcium-Activated Potassium Channels; D010455:Peptides; D024681:Potassium Channels, Calcium-Activated