Article

The effects of the neurosteroids: pregnenolone, progesterone and dehydroepiandrosterone on muscarinic receptor-induced responses in Xenopus oocytes expressing M1 and M3 receptors.

Department of Anesthesiology, School of Medicine, University of Occupational and Environmental Health, Yahatanishiku, Kitakyushu 807-8555, Japan.
Archiv für Experimentelle Pathologie und Pharmakologie (impact factor: 2.65). 04/2005; 371(3):221-8. DOI:10.1007/s00210-005-1022-1 pp.221-8
Source: PubMed

ABSTRACT The neurosteroids pregnenolone, progesterone, and dehydroepiandrosterone (DHEA) occur naturally in the nervous system. They act on neural tissues, participate in neuronal signaling, and are reported to alter neuronal excitability via nongenomic mechanisms. Muscarinic receptors have important roles in neuronal functions in the brain and autonomic nervous system. In this study, we investigated the effects of pregnenolone, progesterone, and DHEA on M(1) and M(3) muscarinic receptors using the Xenopus oocyte expression system. Pregnenolone and progesterone inhibited the acetylcholine (ACh)-mediated responses of M(1) and M(3) receptors expressed in Xenopus oocytes, whereas DHEA did not. The half-maximal inhibitory concentrations (IC(50)) for pregnenolone inhibition of M(1) receptor- and M(3) receptor-mediated currents were 11.4 and 6.0 microM respectively; the IC(50) values for progesterone inhibition of M(1) receptor- and M(3) receptor-mediated currents were 2.5 and 3.0 microM respectively. The selective protein kinase C (PKC) inhibitor GF109203X had little effect on the pregnenolone or progesterone inhibition of the ACh-induced currents in Xenopus oocytes expressing M(1) or M(3) receptors. The inhibitory effects of pregnenolone and progesterone were overcome at higher concentrations of ACh. Pregnenolone and progesterone inhibited the [(3)H]quinuclidinyl benzilate (QNB) binding to M(1) and M(3) receptor expressed in Xenopus oocytes, and Scatchard plot analysis of [(3)H]QNB binding revealed that pregnenolone and progesterone altered the K(d) value and the B(max), indicating noncompetitive inhibition. In conclusion, pregnenolone and progesterone inhibited M(1) and M(3) receptor functions noncompetitively by the mechanism independent of PKC and by interfering with ACh binding to the receptors.

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    Article: Regulation of neurosteroid biosynthesis by neurotransmitters and neuropeptides.
    Jean Luc Do Rego, Jae Young Seong, Delphine Burel, Jerôme Leprince, David Vaudry, Van Luu-The, Marie-Christine Tonon, Kazuyoshi Tsutsui, Georges Pelletier, Hubert Vaudry
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Keywords

ACh)-mediated responses
 
autonomic nervous system
 
half-maximal inhibitory concentrations
 
higher concentrations
 
inhibitory effects
 
Muscarinic receptors
 
neuronal excitability
 
neuronal functions
 
neuronal signaling
 
neurosteroids pregnenolone
 
noncompetitive inhibition
 
nongenomic mechanisms
 
pregnenolone inhibition
 
progesterone inhibited
 
progesterone inhibited M(1)
 
progesterone inhibition
 
Scatchard plot analysis
 
selective protein kinase C
 
Xenopus oocyte expression system
 
Xenopus oocytes