A novel nervous system beta subunit that downregulates human large conductance calcium-dependent potassium channels.
The pore-forming alpha subunits of many ion channels are associated with auxiliary subunits that influence channel expression, targeting, and function. Several different auxiliary (beta) subunits for large conductance calcium-dependent potassium channels of the Slowpoke family have been reported, but none of these beta subunits is expressed extensively in the nervous system. We describe here the cloning and functional characterization of a novel Slowpoke beta4 auxiliary subunit in human and mouse, which exhibits only limited sequence homology with other beta subunits. This beta4 subunit coimmunoprecipitates with human and mouse Slowpoke. beta4 is expressed highly in human and monkey brain in a pattern that overlaps strikingly with Slowpoke alpha subunit, but in contrast to other Slowpoke beta subunits, it is expressed little (if at all) outside the nervous system. Also in contrast to other beta subunits, beta4 downregulates Slowpoke channel activity by shifting its activation range to more depolarized voltages and slowing its activation kinetics. beta4 may be important for the critical roles played by Slowpoke channels in the regulation of neuronal excitability and neurotransmitter release.
Weiger
T M
TM
Department of Biochemistry and Volen Center for Complex Systems, Brandeis University, Waltham, Massachusetts 02454, USA.
Holmqvist
M H
MH
Levitan
I B
IB
Clark
F T
FT
Sprague
S
S
Huang
W J
WJ
Ge
P
P
Wang
C
C
Lawson
D
D
Jurman
M E
ME
Glucksmann
M A
MA
Silos-Santiago
I
I
DiStefano
P S
PS
Curtis
R
R
D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D018999:Charybdotoxin / Q000494:pharmacology; D003001:Cloning, Molecular; D015536:Down-Regulation / Q000235:genetics*; D004594:Electrophysiology; D000939:Epitopes / Q000235:genetics; D015870:Gene Expression / Q000502:physiology; D000882:Haplorhini; D006801:Humans; D017403:In Situ Hybridization; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology; D007668:Kidney / Q000166:cytology; D007700:Kinetics; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; D051038:Large-Conductance Calcium-Activated Potassium Channel beta Subunits; D051036:Large-Conductance Calcium-Activated Potassium Channels; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008969:Molecular Sequence Data; D009474:Neurons / Q000737:chemistry / Q000378:metabolism*; D010455:Peptides / Q000494:pharmacology; D015221:Potassium Channels / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D024681:Potassium Channels, Calcium-Activated; D020836:Protein Structure, Quaternary; D012333:RNA, Messenger / Q000032:analysis; D017422:Sequence Analysis, DNA
D000939:Epitopes; C494841:KCNMA1 protein, human; C494843:Kcnmb4 protein, mouse; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; D051038:Large-Conductance Calcium-Activated Potassium Channel beta Subunits; D051036:Large-Conductance Calcium-Activated Potassium Channels; D010455:Peptides; D015221:Potassium Channels; D024681:Potassium Channels, Calcium-Activated; D012333:RNA, Messenger; D018999:Charybdotoxin; C064719:iberiotoxin