title: Zn2+ activates large conductance Ca2+-activated K+ channel via an intracellular domain.
abstract: Zinc is an essential trace element and plays crucial roles in normal development, often as an integral structural component of transcription factors and enzymes. Recent evidence suggests that intracellular Zn(2+) functions as a signaling molecule, mediating a variety of important physiological phenomena. However, the immediate effectors of intracellular Zn(2+) signaling are not well known. We show here that intracellular Zn(2+) potently and reversibly activates large-conductance voltage- and Ca(2+)-activated Slo1 K(+) (BK) channels. The full effect of Zn(2+) requires His(365) in the RCK1 (regulator of conductance for K(+)) domain of the channel. Furthermore, mutation of two nearby acidic residues, Asp(367) and Glu(399), also reduced activation of the channel by Zn(2+), suggesting a possible structural arrangement for Zn(2+) binding by the aforementioned residues. Extracellular Zn(2+) activated Slo1 BK channels when coexpressed with Zn(2+)-permeable TRPM7 (transient receptor potential melastatin 7) channels. The results thus demonstrate that Slo1 BK channels represent a positive and direct effector of Zn(2+) signaling and may participate in sculpting cellular response to an increase in intracellular Zn(2+) concentration.
authors.affiliation: Department of Physiology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. shangwei@mail.med.upenn.edu
authors.forename: Shangwei
authors.initials: S
authors.lastname: Hou
authors.forename: Leif E
authors.initials: LE
authors.lastname: Vigeland
authors.forename: Guangping
authors.initials: G
authors.lastname: Zhang
authors.forename: Rong
authors.initials: R
authors.lastname: Xu
authors.forename: Min
authors.initials: M
authors.lastname: Li
authors.forename: Stefan H
authors.initials: SH
authors.lastname: Heinemann
authors.forename: Toshinori
authors.initials: T
authors.lastname: Hoshi
mesh_terms: D000818:Animals; D002460:Cell Line; D006639:Histidine; D006801:Humans; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits / Q000502:physiology*; D051379:Mice; D024681:Potassium Channels, Calcium-Activated / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D051381:Rats; D015398:Signal Transduction; D050053:TRPM Cation Channels / Q000378:metabolism; D015032:Zinc / Q000494:pharmacology*
chemical_list: C494841:KCNMA1 protein, human; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; D024681:Potassium Channels, Calcium-Activated; D050053:TRPM Cation Channels; D006639:Histidine; C486584:Trpm7 protein, rat; D015032:Zinc