Phenotypic alteration of a human BK (hSlo) channel by hSlobeta subunit coexpression: changes in blocker sensitivity, activation/relaxation and inactivation kinetics, and protein kinase A modulation.

The Journal of neuroscience : the official journal of the Society for Neuroscience ·Vol. 16 ·No. 15 ·1996-08-01 ·Pages 4543-50

Dworetzky SI, Boissard CG, Lum-Ragan JT, McKay MC, Post-Munson DJ, Trojnacki JT, Chang CP, Gribkoff VK

Abstract

A human homolog of the large-conductance calcium-activated potassium (BK) channel beta subunit (hSlobeta) was cloned, and its effects on a human BK channel (hSlo) phenotype are reported. Coexpression of hSlo and hSlobeta, in both oocytes and human embryonic kidney 293 cells, resulted in increased Ca2+ sensitivity, marked slowing of BK channel activation and relaxation, and significant reduction in slow inactivation. In addition, coexpression changed the pharmacology of the BK channel phenotype: hSlo-mediated currents in oocytes were more sensitive to the peptide toxin iberiotoxin than were hSlo + hSlobeta currents, and the potency of blockade by the alkaloid BK blocker tetrandrine was much greater on hSlo + hSlobeta- mediated currents compared with hSlo currents alone. No significant differences in the response to charybdotoxin or the BK channel opener NS1619 were observed. Modulation of BK channel activity by phosphorylation was also affected by the presence of the hSlobeta subunit. Application of cAMP-dependent protein kinase increased P(OPEN) of hSlo channels, but decreased P(OPEN)of most hSlo + hSlobeta channels. Taken together, these altered characteristics may explain some of the wide diversity of BK channel phenotypes observed in native tissues.

MeSH Terms

Alkaloids/pharmacology Amino Acid Sequence Base Sequence Benzylisoquinolines Calcium/physiology Calcium Channel Blockers/pharmacology Cyclic AMP-Dependent Protein Kinases/metabolism Dose-Response Relationship, Drug Humans Molecular Sequence Data Phenotype Potassium Channels/physiology

Chemicals

Alkaloids Benzylisoquinolines Calcium Channel Blockers Potassium Channels tetrandrine Cyclic AMP-Dependent Protein Kinases Calcium

Authors & Affiliations

8 authors, click to expand affiliations / ORCID

Dworetzky S I

Central Nervous System Drug Discovery, Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, Connecticut 06492, USA.

Boissard C G

Lum-Ragan J T

McKay M C

Post-Munson D J

Trojnacki J T

Chang C P

Gribkoff V K

References (29)

29 references, click to expand

An analysis of 5'-noncoding sequences from 699 vertebrate messenger RNAs.
Nucleic Acids Res. 1987 Oct 26;15(20):8125-48 PMID: 3313277
A family of calcium-dependent potassium channels from rat brain.
Neuron. 1989 Jan;2(1):1031-41 PMID: 2624739
An essential 'set' of K+ channels conserved in flies, mice and humans.
Trends Neurosci. 1992 May;15(5):161-6 PMID: 1377421
Tetrandrine blocks a slow, large-conductance, Ca(2+)-activated potassium channel besides inhibiting a non-inactivating Ca2+ current in isolated nerve terminals of the rat neurohypophysis.
Pflugers Arch. 1992 Sep;421(6):558-65 PMID: 1331975
Charybdotoxin, a protein inhibitor of single Ca2+-activated K+ channels from mammalian skeletal muscle.
Nature. 1985 Jan 24-30;313(6000):316-8 PMID: 2578618
Varieties of calcium-activated potassium channels.
Annu Rev Physiol. 1989;51:385-99 PMID: 2653189
Functional differences among alternatively spliced variants of Slowpoke, a Drosophila calcium-activated potassium channel.
J Biol Chem. 1994 Aug 12;269(32):20347-51 PMID: 8051129
Purification and characterization of a unique, potent, peptidyl probe for the high conductance calcium-activated potassium channel from venom of the scorpion Buthus tamulus.
J Biol Chem. 1990 Jul 5;265(19):11083-90 PMID: 1694175
Inactivation properties of voltage-gated K+ channels altered by presence of beta-subunit.
Nature. 1994 May 26;369(6478):289-94 PMID: 8183366
A calcium switch for the functional coupling between alpha (hslo) and beta subunits (KV,Ca beta) of maxi K channels.
FEBS Lett. 1996 Mar 11;382(1-2):84-8 PMID: 8612769
Mechanism of iberiotoxin block of the large-conductance calcium-activated potassium channel from bovine aortic smooth muscle.
Biochemistry. 1992 Jul 28;31(29):6719-27 PMID: 1379069
Molecular biology of voltage-dependent potassium channels.
Physiol Rev. 1992 Oct;72(4 Suppl):S69-88 PMID: 1438587
mSlo, a complex mouse gene encoding "maxi" calcium-activated potassium channels.
Science. 1993 Jul 9;261(5118):221-4 PMID: 7687074
Presynaptic calcium signals and transmitter release are modulated by calcium-activated potassium channels.
J Neurosci. 1992 Jan;12(1):297-305 PMID: 1370323
Functional role of the beta subunit of high conductance calcium-activated potassium channels.
Neuron. 1995 Mar;14(3):645-50 PMID: 7695911
A human calcium-activated potassium channel gene expressed in vascular smooth muscle.
Am J Physiol. 1995 Sep;269(3 Pt 2):H767-77 PMID: 7573516
Modulation of calcium-activated potassium channels from rat brain by protein kinase A and phosphatase 2A.
J Neurosci. 1991 Jun;11(6):1627-35 PMID: 1646298
Distinct effects of Ca2+ and voltage on the activation and deactivation of cloned Ca(2+)-activated K+ channels.
J Physiol. 1995 Dec 1;489 ( Pt 2):403-18 PMID: 8847636
Cloning, expression, and distribution of functionally distinct Ca(2+)-activated K+ channel isoforms from human brain.
Neuron. 1994 Dec;13(6):1315-30 PMID: 7993625
Primary sequence and immunological characterization of beta-subunit of high conductance Ca(2+)-activated K+ channel from smooth muscle.
J Biol Chem. 1994 Jun 24;269(25):17274-8 PMID: 8006036
Opening of large-conductance calcium-activated potassium channels by the substituted benzimidazolone NS004.
J Neurophysiol. 1994 May;71(5):1873-82 PMID: 8064354
Cloning and expression of a human large-conductance calcium-activated potassium channel.
Brain Res Mol Brain Res. 1994 Nov;27(1):189-93 PMID: 7877450
Selective activation of Ca(2+)-dependent K+ channels by novel benzimidazolone.
Eur J Pharmacol. 1994 Jan 4;251(1):53-9 PMID: 8137869
Improved patch-clamp techniques for high-resolution current recording from cells and cell-free membrane patches.
Pflugers Arch. 1981 Aug;391(2):85-100 PMID: 6270629
Calcium-activated potassium channels expressed from cloned complementary DNAs.
Neuron. 1992 Aug;9(2):209-16 PMID: 1497890
A calcium-activated potassium channel causes frequency-dependent action-potential failures in a mammalian nerve terminal.
J Neurophysiol. 1993 Jul;70(1):284-98 PMID: 8395581
Cloning and characterization of human and mouse homologs of the Drosophila calcium-activated potassium channel gene, slowpoke.
Hum Mol Genet. 1994 Aug;3(8):1239-43 PMID: 7987297
Synthesis and structural characterization of charybdotoxin, a potent peptidyl inhibitor of the high conductance Ca2(+)-activated K+ channel.
J Biol Chem. 1990 Nov 5;265(31):18745-8 PMID: 1699936
A component of calcium-activated potassium channels encoded by the Drosophila slo locus.
Science. 1991 Aug 2;253(5019):551-5 PMID: 1857984

Article Info

Journal

The Journal of neuroscience : the official journal of the Society for Neuroscience

Abbr.

J Neurosci

ISSN

0270-6474

Published

1996-08-01

Pages

4543-50

Language

English

Region

United States

NLM ID

8102140

PMCID

PMC6579031

Subset

External Links

PubMed source PMC Full Text View journal details

Analysis Services

Phenotypic alteration of a human BK (hSlo) channel by hSlobeta subunit coexpression: changes in blocker sensitivity, activation/relaxation and inactivation kinetics, and protein kinase A modulation.

Contact

WeChat Official Account