Zn2+ activates large conductance Ca2+-activated K+ channel via an intracellular domain.
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.
Hou
Shangwei
S
Department of Physiology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. shangwei@mail.med.upenn.edu
Vigeland
Leif E
LE
Zhang
Guangping
G
Xu
Rong
R
Li
Min
M
Heinemann
Stefan H
SH
Hoshi
Toshinori
T
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*
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