Divalent heavy metal cations block the TRPV1 Ca2+ channel

László Pecze, Zoltán Winter, Katalin Jósvay, F. Ötvös, Csongor Kolozsi, C. Vízler, D. Budai, Tamás Letoha, G. Dombi, G. Szakonyi, Zoltán Oláh

Research output: Article

6 Citations (Scopus)

Abstract

Transient receptor potential vanilloid 1 (TRPV1) is a non-selective cation channel involved in pain sensation and in a wide range of non-pain-related physiological and pathological conditions. The aim of the present study was to explore the effects of selected heavy metal cations on the function of TRPV1. The cations ranked in the following sequence of pore-blocking activity: Co 2+ [half-maximal inhibitory concentration (IC50)013 μM]>Cd 2+ (IC500 38 μM)>Ni2+ (IC50062 μM)>Cu 2+(IC500200 μM). Zn2+ proved to be a weak (IC50027 μM) and only partial inhibitor of the channel function, whereas Mg 2+, Mn2+ and La3+ did not exhibit any substantial effect. Co2+, the most potent channel blocker, was able not only to compete with Ca2+ but also to pass with it through the open channel of TRPV1. In response to heat activation or vanilloid treatment, Co2+ accumulation was verified in TRPV1-transfected cell lines and in the TRPV1+ dorsal root ganglion neurons. The inhibitory effect was also demonstrated in vivo. Co2+ applied together with vanilloid agonists attenuated the nocifensive eye wipe response in mice. Different rat TRPV1 pore point mutants (Y627W, N628W, D646N and E651W) were created that can validate the binding site of previously used channel blockers in agonist-evoked 45Ca2+ influx assays in cells expressing TRPV1. The IC50 of Co2+ on these point mutants were determined to be reasonably comparable to those on the wild type, which suggests that divalent cations passing through the TRPV1 channel use the same negatively charged amino acids as Ca2+.

Original languageEnglish
Pages (from-to)451-461
Number of pages11
JournalBiological Trace Element Research
Volume151
Issue number3
DOIs
Publication statusPublished - 2013

Fingerprint

Heavy Metals
Cations
Inhibitory Concentration 50
Cells
Transient Receptor Potential Channels
Divalent Cations
Spinal Ganglia
vanilloid receptor subtype 1
Neurons
Rats
Assays
Hot Temperature
Chemical activation
Binding Sites
Amino Acids
Pain
Cell Line

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Inorganic Chemistry
  • Biochemistry, medical
  • Endocrinology, Diabetes and Metabolism

Cite this

Divalent heavy metal cations block the TRPV1 Ca2+ channel. / Pecze, László; Winter, Zoltán; Jósvay, Katalin; Ötvös, F.; Kolozsi, Csongor; Vízler, C.; Budai, D.; Letoha, Tamás; Dombi, G.; Szakonyi, G.; Oláh, Zoltán.

In: Biological Trace Element Research, Vol. 151, No. 3, 2013, p. 451-461.

Research output: Article

Pecze, László ; Winter, Zoltán ; Jósvay, Katalin ; Ötvös, F. ; Kolozsi, Csongor ; Vízler, C. ; Budai, D. ; Letoha, Tamás ; Dombi, G. ; Szakonyi, G. ; Oláh, Zoltán. / Divalent heavy metal cations block the TRPV1 Ca2+ channel. In: Biological Trace Element Research. 2013 ; Vol. 151, No. 3. pp. 451-461.
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AU - Pecze, László

AU - Winter, Zoltán

AU - Jósvay, Katalin

AU - Ötvös, F.

AU - Kolozsi, Csongor

AU - Vízler, C.

AU - Budai, D.

AU - Letoha, Tamás

AU - Dombi, G.

AU - Szakonyi, G.

AU - Oláh, Zoltán

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AB - Transient receptor potential vanilloid 1 (TRPV1) is a non-selective cation channel involved in pain sensation and in a wide range of non-pain-related physiological and pathological conditions. The aim of the present study was to explore the effects of selected heavy metal cations on the function of TRPV1. The cations ranked in the following sequence of pore-blocking activity: Co 2+ [half-maximal inhibitory concentration (IC50)013 μM]>Cd 2+ (IC500 38 μM)>Ni2+ (IC50062 μM)>Cu 2+(IC500200 μM). Zn2+ proved to be a weak (IC50027 μM) and only partial inhibitor of the channel function, whereas Mg 2+, Mn2+ and La3+ did not exhibit any substantial effect. Co2+, the most potent channel blocker, was able not only to compete with Ca2+ but also to pass with it through the open channel of TRPV1. In response to heat activation or vanilloid treatment, Co2+ accumulation was verified in TRPV1-transfected cell lines and in the TRPV1+ dorsal root ganglion neurons. The inhibitory effect was also demonstrated in vivo. Co2+ applied together with vanilloid agonists attenuated the nocifensive eye wipe response in mice. Different rat TRPV1 pore point mutants (Y627W, N628W, D646N and E651W) were created that can validate the binding site of previously used channel blockers in agonist-evoked 45Ca2+ influx assays in cells expressing TRPV1. The IC50 of Co2+ on these point mutants were determined to be reasonably comparable to those on the wild type, which suggests that divalent cations passing through the TRPV1 channel use the same negatively charged amino acids as Ca2+.

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