Pregnenolone sulphate-independent inhibition of TRPM3 channels by progesterone

Yasser Majeed, Sarka Tumova, Ben L. Green, Victoria A.L. Seymour, Daniel M. Woods, Anil K. Agarwal, Jacqueline Naylor, Shannon Jiang, Helen M. Picton, Karen E. Porter, David J. O'Regan, Katsuhiko Muraki, Colin W.G. Fishwick, David J. Beech

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

Transient Receptor Potential Melastatin 3 (TRPM3) is a widely expressed calcium-permeable non-selective cation channel that is stimulated by high concentrations of nifedipine or by physiological steroids that include pregnenolone sulphate. Here we sought to identify steroids that inhibit TRPM3. Channel activity was studied using calcium-measurement and patch-clamp techniques. Progesterone (0.01-10μM) suppressed TRPM3 activity evoked by pregnenolone sulphate. Progesterone metabolites and 17β-oestradiol were also inhibitory but the effects were relatively small. Dihydrotestosterone was an inhibitor at concentrations higher than 1μM. Corticosteroids lacked effect. Overlay assays indicated that pregnenolone sulphate, progesterone and dihydrotestosterone bound to TRPM3. In contrast to dihydrotestosterone, progesterone inhibited nifedipine-evoked TRPM3 activity or activity in the absence of an exogenous activator, suggesting a pregnenolone sulphate-independent mechanism of action. Dihydrotestosterone, like a non-steroid look-alike compound, acted as a competitive antagonist at the pregnenolone sulphate binding site. Progesterone inhibited endogenous TRPM3 in vascular smooth muscle cells. Relevance of TRPM3 or the progesterone effect to ovarian cells, which have been suggested to express TRPM3, was not identified. The data further define a chemical framework for competition with pregnenolone sulphate at TRPM3 and expand knowledge of steroid interactions with TRPM3, suggesting direct steroid binding and pregnenolone sulphate-independent inhibition by progesterone.

Original languageEnglish
Pages (from-to)1-11
Number of pages11
JournalCell Calcium
Volume51
Issue number1
DOIs
Publication statusPublished - 1 Jan 2012
Externally publishedYes

Fingerprint

Progesterone
Dihydrotestosterone
Steroids
Nifedipine
Calcium
Patch-Clamp Techniques
pregnenolone sulfate
Vascular Smooth Muscle
Smooth Muscle Myocytes
Cations
Estradiol
Adrenal Cortex Hormones
Binding Sites

Keywords

  • Calcium influx
  • Cationic channel
  • Pregnenolone
  • Progesterone
  • Steroid
  • Transient receptor potential

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

Cite this

Majeed, Y., Tumova, S., Green, B. L., Seymour, V. A. L., Woods, D. M., Agarwal, A. K., ... Beech, D. J. (2012). Pregnenolone sulphate-independent inhibition of TRPM3 channels by progesterone. Cell Calcium, 51(1), 1-11. https://doi.org/10.1016/j.ceca.2011.09.005

Pregnenolone sulphate-independent inhibition of TRPM3 channels by progesterone. / Majeed, Yasser; Tumova, Sarka; Green, Ben L.; Seymour, Victoria A.L.; Woods, Daniel M.; Agarwal, Anil K.; Naylor, Jacqueline; Jiang, Shannon; Picton, Helen M.; Porter, Karen E.; O'Regan, David J.; Muraki, Katsuhiko; Fishwick, Colin W.G.; Beech, David J.

In: Cell Calcium, Vol. 51, No. 1, 01.01.2012, p. 1-11.

Research output: Contribution to journalArticle

Majeed, Y, Tumova, S, Green, BL, Seymour, VAL, Woods, DM, Agarwal, AK, Naylor, J, Jiang, S, Picton, HM, Porter, KE, O'Regan, DJ, Muraki, K, Fishwick, CWG & Beech, DJ 2012, 'Pregnenolone sulphate-independent inhibition of TRPM3 channels by progesterone', Cell Calcium, vol. 51, no. 1, pp. 1-11. https://doi.org/10.1016/j.ceca.2011.09.005
Majeed, Yasser ; Tumova, Sarka ; Green, Ben L. ; Seymour, Victoria A.L. ; Woods, Daniel M. ; Agarwal, Anil K. ; Naylor, Jacqueline ; Jiang, Shannon ; Picton, Helen M. ; Porter, Karen E. ; O'Regan, David J. ; Muraki, Katsuhiko ; Fishwick, Colin W.G. ; Beech, David J. / Pregnenolone sulphate-independent inhibition of TRPM3 channels by progesterone. In: Cell Calcium. 2012 ; Vol. 51, No. 1. pp. 1-11.
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