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Vasoregulation by the β1 subunit of the calcium-activated potassium channel

Nature volume 407, pages 870–876 (2000)Cite this article

Abstract

Small arteries exhibit tone, a partially contracted state that is an important determinant of blood pressure. In arterial smooth muscle cells, intracellular calcium paradoxically controls both contraction and relaxation. The mechanisms by which calcium can differentially regulate diverse physiological responses within a single cell remain unresolved. Calcium-dependent relaxation is mediated by local calcium release from the sarcoplasmic reticulum. These ‘calcium sparks’ activate calcium-dependent potassium (BK) channels comprised of α and β1 subunits. Here we show that targeted deletion of the gene for the β1 subunit leads to a decrease in the calcium sensitivity of BK channels, a reduction in functional coupling of calcium sparks to BK channel activation, and increases in arterial tone and blood pressure. The β1 subunit of the BK channel, by tuning the channel's calcium sensitivity, is a key molecular component in translating calcium signals to the central physiological function of vasoregulation.

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Figure 1: Generation of β1 gene knockout mice.
Figure 2: Detection of lacZ gene expression from β1 gene-targeted mice.
Figure 3: Ca2+ and voltage dependence of BK channels in cerebral artery myocytes from control and β1-KO animals.
Figure 4: DHS-1 sensitivity and density of BK channels in cerebral arteries myocytes from control and β1-KO animals.
Figure 5: Decreased coupling of calcium sparks to BK channels in β1-KO myocytes.
Figure 6: β1-KO cerebral arteries are more constricted to pressure.
Figure 7: β1-KO mice show symptoms of hypertension.

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Acknowledgements

We thank B. K. Kobilka of Stanford University for advice; Y. Chen in the Stanford Transgenic Mouse facility for the blastocyst injections; G. Mawe for advice and assistance on isolated artery images; S. Brett Welsh for genotyping and technical assistance; D. Hill-Eubanks for comments on the manuscript and D. P. Regula for paraffin sections of hearts. DHS-1 was provided by Merck Research Laboratories. This work was supported by a grant from the Federation for Anesthesia Education and Research to A.J.P. and by grants from the National Institutes of Health (H.L.B.I. and D.D.K.), National Science Foundation, Totman Medical Trust for Cerebrovascular Research to M.T.N., and an American Heart Association Fellowship to G.P. R.W.A. is an investigator with the Howard Hughes Medical Institute.

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Authors and Affiliations

  1. Department of Molecular and Cellular Physiology and Howard Hughes Medical Institute, Stanford University, Stanford, 94305, California, USA

    Robert Brenner, Steven W. Wiler & Richard W. Aldrich

  2. Department of Pharmacology, College of Medicine, The University of Vermont, Burlington, 05405, Vermont, USA

    Guillermo J. Peréz, Adrian D. Bonev, Delrae M. Eckman & Mark T. Nelson

  3. Department of Pathology, Palo Alto Veterans Administration Healthcare System, Palo Alto, 94305, California

    Jon C. Kosek

  4. Stanford University School of Medicine , Stanford, 94305, California, USA

    Jon C. Kosek

  5. Department of Anesthesia, Stanford University School of Medicine, Stanford, 94305, California, USA

    Andrew J. Patterson

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Correspondence to Richard W. Aldrich.

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Brenner, R., Peréz, G., Bonev, A. et al. Vasoregulation by the β1 subunit of the calcium-activated potassium channel. Nature 407, 870–876 (2000). https://doi.org/10.1038/35038011

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