A neuronal beta subunit (KCNMB4) makes the large conductance, voltage- and Ca2+-activated K+ channel resistant to charybdotoxin and iberiotoxin.
Large conductance voltage and Ca(2+)-activated K(+) (MaxiK) channels couple intracellular Ca(2+) with cellular excitability. They are composed of a pore-forming alpha subunit and modulatory beta subunits. The pore blockers charybdotoxin (CTx) and iberiotoxin (IbTx), at nanomolar concentrations, have been invaluable in unraveling MaxiK channel physiological role in vertebrates. However in mammalian brain, CTx-insensitive MaxiK channels have been described [Reinhart, P. H., Chung, S. & Levitan, I. B. (1989) Neuron 2, 1031-1041], but their molecular basis is unknown. Here we report a human MaxiK channel beta-subunit (beta4), highly expressed in brain, which renders the MaxiK channel alpha-subunit resistant to nanomolar concentrations of CTx and IbTx. The resistance of MaxiK channel to toxin block, a phenotype conferred by the beta4 extracellular loop, results from a dramatic ( approximately 1,000 fold) slowdown of the toxin association. However once bound, the toxin block is apparently irreversible. Thus, unusually high toxin concentrations and long exposure times are necessary to determine the role of "CTx/IbTx-insensitive" MaxiK channels formed by alpha + beta4 subunits.
Meera
P
P
Department of Anesthesiology, Brain Research Institute, University of California, Los Angeles, CA 90095-7115, USA.
Wallner
M
M
Toro
L
L
D000595:Amino Acid Sequence; D000818:Animals; D001921:Brain / Q000502:physiology*; D018999:Charybdotoxin / Q000494:pharmacology*; D003001:Cloning, Molecular; D005260:Female; D006031:Glycosylation; D006801:Humans; 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; D046911:Macromolecular Substances; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008969:Molecular Sequence Data; D009474:Neurons / Q000502:physiology*; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D010455:Peptides / Q000494:pharmacology*; D015221:Potassium Channels / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D024681:Potassium Channels, Calcium-Activated; D014176:Protein Biosynthesis; D017433:Protein Structure, Secondary; D012333:RNA, Messenger / Q000235:genetics; D011994:Recombinant Proteins / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D014158:Transcription, Genetic; D014982:Xenopus laevis
C494841:KCNMA1 protein, human; 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; D046911:Macromolecular Substances; D010455:Peptides; D015221:Potassium Channels; D024681:Potassium Channels, Calcium-Activated; D012333:RNA, Messenger; D011994:Recombinant Proteins; D018999:Charybdotoxin; C064719:iberiotoxin