Center for Bioinformatics at KU

As part of our public Seminar Series
http://bioinformatics.ku.edu/seminars

October 20, Tue 2009
1:00 pm, MRB 100 Conference Room

Dr. Toshi Hoshi

Department of Physiology, University of Pennsylvania

Activation of the large-conductance Ca²⁺- and voltage-gated Slo1 K⁺ channel by Ca²⁺, H⁺ and carbon monoxide

Large-conductance Ca²⁺- and voltage-gated K⁺ (Slo1 BK) channels are tetrameric transmembrane K⁺-selective ion channel proteins opened by an increase in intracellular Ca²⁺ and/or plasma membrane depolarization, and contribute to a variety of physiological phenomena. The physiological versatility of the channel is in part conferred by its allosteric gating mechanism encompassing concerted opening and closing of the ion conduction gate, activation of transmembrane voltage sensors and binding of multiple ligands to the cytoplasmic sensors. The gating machinery function is directly modulated by a variety of physiological signaling molecules including free heme/hemin, carbon monoxide and H⁺. For example, nanomolar concentrations of free heme/hemin acutely regulate the channel activity in part by weakening the strength of allosteric coupling between the channel’s gate and voltage sensors. In contrast, carbon monoxide and H⁺promote channel opening by partially mimicking the action of intracellular Ca²⁺. The Ca²⁺-dependent activation of the Slo1 BK channel is typically considered to involve two distinct Ca²⁺ sensors: RCK1 sensor and Ca²⁺ bowl sensor. The stimulatory effects of carbon monoxide and H⁺ are dependent on the RCK1 Ca²⁺ sensor. In particular, two His residues located in the RCK1 Ca²⁺ sensor are essential. Activation of the channel by H⁺ may involve movement of the aforementioned two His residues by several angstroms. We postulate that the RCK1 Ca²⁺ sensor is a multi-ligand sensor capable of detecting Ca²⁺ carbon monoxide and H⁺.