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A structural motif in the C-terminal tail of slo1 confers carbon monoxide sensitivity to human BKCa channels

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Abstract

Carbon monoxide (CO) is a potent activator of large conductance, calcium-dependent potassium (BKCa) channels of vascular myocytes and carotid body glomus cells or when heterologously expressed. Using the human BKCa channel α1-subunit (hSlo1; KCNMA1) stably and transiently expressed in human embryonic kidney 293 cells, the mechanism and structural basis of channel activation by CO was investigated in inside–out, excised membrane patches. Activation by CO was concentration dependent (EC50 ∼20 μM), rapid, reversible, and evoked a shift in the V0.5 of −20 mV. CO evoked no changes in either single channel conductance or in deactivation rate but augmented channel activation rate. Activation was independent of the redox state of the channel, or associated compounds/protein partners, and was partially dependent on [Ca2+]i in the physiological range (100–1,000 nM). Importantly, CO “super-stimulated” BKCa activity even in saturating [Ca2+]i. Single or double mutation of two histidine residues previously implicated in CO sensing did not suppress CO activation but replacing the S9–S10 module of the C-terminal of Slo1 with that of Slo3 completely prevented the action of CO. These findings show that a motif in the S9–S10 part of the C-terminal is essential for CO activation and suggest that this gas transmitter activates the BKCa channel by redox-independent changes in gating.

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References

  1. Barbe C, Al-Hashem F, Conway AF, Dubuis E, Vandier C, Kumar P (2002) A possible dual site of action for carbon monoxide-mediated chemoexcitation in the rat carotid body. J Physiol 543:933–945

    Article  PubMed  CAS  Google Scholar 

  2. Boczkowski J, Poderoso JJ, Motterlini R (2006) CO-metal interaction: vital signaling from a lethal gas. Trends Biochem Sci 31:614–621

    Article  PubMed  CAS  Google Scholar 

  3. Dubuis E, Potier M, Wang R, Vandier C (2005) Continuous inhalation of carbon monoxide attenuates hypoxic pulmonary hypertension development presumably through activation of BKCa channels. Cardiovasc Res 65:751–761

    Article  PubMed  CAS  Google Scholar 

  4. Evans IP, Spencer A, Wilkinson G (1973) Dichlorotetrakis(dimethyl sulphoxide)ruthenium(II) and its use as a source material for some new ruthenium(II) complexes. J Chem Soc Dalton Trans 2:204–208

    Article  Google Scholar 

  5. Foresti R, Hammad J, Clark JE, Johnson TR, Mann BE, Friebe A, Green CJ, Motterlini R (2004) Vasoactive properties of CORM-3, a novel water-soluble carbon monoxide-releasing molecule. Br J Pharmacol 142:453–460

    Article  PubMed  CAS  Google Scholar 

  6. Horrigan FT, Heinemann SH, Hoshi T (2005) Heme regulates allosteric activation of the Slo1 BK channel. J Gen Physiol 126:7–21

    Article  PubMed  CAS  Google Scholar 

  7. Horrigan FT, Heinemann SH, Hoshi T (2005) Heme regulates allosteric activation of the Slo1 BK channel. J Gen Physiol 126:7–21

    Article  PubMed  CAS  Google Scholar 

  8. Jaggar JH, Leffler CW, Cheranov SY, Tcheranova DES, Cheng X (2002) Carbon monoxide dilates cerebral arterioles by enhancing the coupling of Ca2+ sparks to Ca2+-activated K+ channels. Circ Res 91:610–617

    Article  PubMed  CAS  Google Scholar 

  9. Jaggar JH, Li A, Parfenova H, Liu J, Umstot ES, Dopico AM, Leffler CW (2005) Heme is a carbon monoxide receptor for large-conductance Ca2+-activated K+ channels. Circ Res 97:805–812

    Article  PubMed  CAS  Google Scholar 

  10. Kemp PJ, Iles D, Peers C (2004) Oxygen sensing by human recombinant K+ channels: assessment of the use of stable cell lines. Methods Enzymol 381: 257–274

    Article  PubMed  CAS  Google Scholar 

  11. Leffler CW, Parfenova H, Jaggar JH, Wang R (2006) Carbon monoxide and hydrogen sulfide: gaseous messengers in cerebrovascular circulation. J Appl Physiol 100:1065–1076

    Article  PubMed  CAS  Google Scholar 

  12. Lewis A, Peers C, Ashford MLJ, Kemp PJ (2002) Hypoxia inhibits human recombinant maxi K+ channels by a mechanism which is membrane delimited and Ca2+-sensitive. J Physiol 540:771–780

    Article  PubMed  CAS  Google Scholar 

  13. Maines MD, Trakshel GM, Kutty RK (1986) Characterization of two constitutive forms of rat liver microsomal heme oxygenase. Only one molecular species of the enzyme is inducible. J Biol Chem 261:411–419

    PubMed  CAS  Google Scholar 

  14. Mann BE, Motterlini R (2007) CO and NO in medicine. Chem Comm, in press. DOI 10.1039/b704873d

  15. McCoubrey WK Jr, Huang TJ, Maines MD (1997) Isolation and characterization of a cDNA from the rat brain that encodes hemoprotein heme oxygenase-3. Eur J Biochem 247:725–732

    Article  PubMed  CAS  Google Scholar 

  16. Mojet MH, Mills E, Duchen MR (1997) Hypoxia-induced catecholamine secretion in isolated newborn rat adrenal chromaffin cells is mimicked by inhibition of mitochondrial respiration. J Physiol 504:175–189

    Article  PubMed  CAS  Google Scholar 

  17. Moss BL, Magleby KL (2001) Gating and conductance properties of BK channels are modulated by the S9–S10 tail domain of the alpha subunit. A study of mSlo1 and mSlo3 wild-type and chimeric channels. J Gen Physiol 118:711–734

    Article  PubMed  CAS  Google Scholar 

  18. Prabhakar NR, Dinerman JL, Agani FH, Snyder SH (1995) Carbon monoxide: a role in carotid body chemoreception. Proc Natl Acad Sci USA 92:1994–1997

    Article  PubMed  CAS  Google Scholar 

  19. Riesco-Fagundo AM, Perez-Garcia MT, Gonzalez C, Lopez-Lopez JR (2001) O2 modulates large-conductance Ca2+-dependent K+ channels of rat chemoreceptor cells by a membrane-restricted and CO-sensitive mechanism. Circ Res 89:430–436

    Article  PubMed  CAS  Google Scholar 

  20. Ryter SW, Alam J, Choi AM (2006) Heme oxygenase-1/carbon monoxide: from basic science to therapeutic applications. Physiol Rev 86:583–650

    Article  PubMed  CAS  Google Scholar 

  21. Schreiber M, Wei A, Yuan A, Gaut J, Saito M, Salkoff L (1998) Slo3, a novel pH-sensitive K+ channel from mammalian spermatocytes. J Biol Chem 273:3509–3516

    Article  PubMed  CAS  Google Scholar 

  22. Tang XD, Xu R, Reynolds MF, Garcia ML, Heinemann SH, Hoshi T (2003) Haem can bind to and inhibit mammalian calcium-dependent Slo1 BK channels. Nature 425:531–535

    Article  PubMed  CAS  Google Scholar 

  23. Tenhunen R, Marver HS, Schmid R (1968) The enzymatic conversion of heme to bilirubin by microsomal heme oxygenase. Proc Natl Acad Sci USA 61:748–755

    Article  PubMed  CAS  Google Scholar 

  24. Wang R, Wang Z, Wu L (1997) Carbon monoxide-induced vasorelaxation and the underlying mechanisms. Br J Pharmacol 121:927–934

    Article  PubMed  CAS  Google Scholar 

  25. Wang R, Wu L (1997) The chemical modification of KCa channels by carbon monoxide in vascular smooth muscle cells. J Biol Chem 272:8222–8226

    Article  PubMed  CAS  Google Scholar 

  26. Wang R, Wu L (1997) The chemical modification of KCa channels by carbon monoxide in vascular smooth muscle cells. J Biol Chem 272:8222–8226

    Article  PubMed  CAS  Google Scholar 

  27. Wang R, Wu L, Wang Z (1997) The direct effect of carbon monoxide on KCa channels in vascular smooth muscle cells. Pflugers Arch 434:285–291

    Article  PubMed  CAS  Google Scholar 

  28. Williams SE, Wootton P, Mason HS, Bould J, Iles DE, Riccardi D, Peers C, Kemp PJ (2004) Hemoxygenase-2 is an oxygen sensor for a calcium-sensitive potassium channel. Science 306:2093–2097

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

Funded by the British Heart Foundation Programme Grant RG/03/001.

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Authors and Affiliations

  1. School of Biosciences, Cardiff University, Museum Avenue, Cardiff, CF10 3US, UK

    Sandile E. Williams, Stephen P. Brazier, Nian Baban, Vsevolod Telezhkin, Carsten T. Müller, Daniela Riccardi & Paul J. Kemp

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  1. Sandile E. Williams
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  2. Stephen P. Brazier
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  3. Nian Baban
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  5. Carsten T. Müller
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  7. Paul J. Kemp
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Correspondence to Paul J. Kemp.

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Williams, S.E., Brazier, S.P., Baban, N. et al. A structural motif in the C-terminal tail of slo1 confers carbon monoxide sensitivity to human BKCa channels. Pflugers Arch - Eur J Physiol 456, 561–572 (2008). https://doi.org/10.1007/s00424-007-0439-4

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  • DOI: https://doi.org/10.1007/s00424-007-0439-4

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