Residual Ca2+ channel current modulation by megestrol acetate via a G-protein alpha s-subunit in rat hypothalamic neurones.
AUTOR(ES)
Costa, A M
RESUMO
1. The inhibition of voltage-activated Ca2+ channel currents by the orally active progesterone derivative, megestrol acetate (MA), was examined in freshly dissociated rat ventromedial hypothalamic nucleus (VMN) neurones using the whole-cell voltage-clamp technique with 10 mM Ba2+ as the charge carrier. 2. The steady-state inhibition of the peak high-threshold Ca2+ channel current evoked by depolarization from -80 to -10 mV by MA increased in a concentration-dependent fashion. MA inhibited a fraction of the whole-cell Ca2+ channel current while progesterone had no effect on the peak Ca2+ channel current (7% at 10 microM). The low-threshold Ca2+ (T-type) current, evoked from -100 to -30 mV, was unaffected by MA. 3. Intracellular dialysis with MA had no effect on the Ca2+ channel current. Concomitant extracellular perfusion of MA showed normal inhibitory activity, suggesting that the MA binding site can only be accessed extracellularly. 4. The high-threshold Ca2+ channel current in VMN neurones was found to consist of four pharmacologically distinguishable components: an N-type current, an L-type current, a P-type current, and a residual current. MA had no effect on the N-, L- and P-type Ca2+ channel currents, but inhibited the residual current. 5. In neurones isolated from cholera toxin-treated animals, the MA-induced inhibition of the Ca2+ channel current was significantly diminished, suggesting a G-protein alpha S-subunit involvement. 6. Treatment with antisense phosphothio-oligodeoxynucleotides to the G alpha S-subunit (antisense-G alpha S) significantly reduced the MA-induced inhibition of the Ca2+ channel current. Treatment with either sense-G alpha S or antisense-G alpha 11 had no effect, confirming a G alpha S-subunit involvement. 7. These results suggest that appetite enhancement induced by MA in cachectic patients may in part be due to a novel central nervous system action, that is, inhibition of a fraction of the whole-cell Ca2+ channel current to attenuate the firing of VMN neurones that may be involved in satiety mechanisms.
ACESSO AO ARTIGO
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1156573Documentos Relacionados
- Muscarine modulation by a G-protein alpha-subunit of delayed rectifier K+ current in rat ventromedial hypothalamic neurones.
- Muscarinic M-current inhibition via G alpha q/11 and alpha-adrenoceptor inhibition of Ca2+ current via G alpha o in rat sympathetic neurones.
- Assignment of muscarinic receptor subtypes mediating G-protein modulation of Ca2+ channels by using knockout mice
- Structural Determinants of G-protein α Subunit Selectivity by Regulator of G-protein Signaling 2 (RGS2)*
- Characterization of Ca2+ channel currents in cultured rat cerebellar granule neurones.