Defining the BK channel domains required for beta1-subunit modulation.
In a wide variety of cell types, including neurons and smooth muscle cells, activation of the large-conductance voltage- and Ca(2+)-activated K(+) (BK) channels causes transient membrane hyperpolarization, thereby regulating cellular excitability. Similar to other voltage-gated ion channels, BK channels, a tetramer of alpha-subunits, associate with auxiliary beta-subunits in a tissue-specific manner, modifying the channel's gating properties. The BK beta1-subunit, which is expressed in smooth muscle, increases the apparent Ca(2+) sensitivity (marked by a hyperpolarizing shift in the conductance-voltage relationship at a given Ca(2+) concentration), slows macroscopic activation and deactivation, and is required for channel activation by 17beta-estradiol. The beta1-subunit is essential for normal regulation of vascular smooth muscle contractility and blood pressure. Little is known, however, about the molecular mechanisms of beta1-subunit modulation of alpha-subunits. Here we show that the beta1-subunit's modulation of the Ca(2+) and 17beta-estradiol sensitivities can be dissociated from its effects on gating kinetics by truncation of the alpha-subunit's extracellular N-terminal residues. The BK alpha-subunit N terminus interacts uniquely with the beta1-subunit: beta2 regulation of the alpha-subunit is unaltered by truncation of the N terminus. Although the functional interaction of alpha and beta1 requires the N-terminal tail of alpha, the physical association requires the S1, S2, and S3 transmembrane helices of alpha.
Morrow
John P
JP
Division of Cardiology, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
Zakharov
Sergey I
SI
Liu
Guoxia
G
Yang
Lin
L
Sok
Andrea J
AJ
Marx
Steven O
SO
D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D004594:Electrophysiology; D004958:Estradiol / Q000494:pharmacology; D006801:Humans; D015640:Ion Channel Gating; D007700:Kinetics; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D018408:Patch-Clamp Techniques; D024681:Potassium Channels, Calcium-Activated / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism*
D024681:Potassium Channels, Calcium-Activated; D021122:Protein Subunits; D004958:Estradiol