Amn. Costa et al., RESIDUAL CA2-ACETATE VIA A G-PROTEIN ALPHA(S)-SUBUNIT IN RAT HYPOTHALAMIC NEURONS( CHANNEL CURRENT MODULATION BY MEGESTROL), Journal of physiology, 487(2), 1995, pp. 291-303
1. The inhibition of voltage-activated Ca2+ channel currents by the or
ally active progesterone derivative, megestrol acetate (MA), was exami
ned in freshly dissociated rat ventromedial hypothalamic nucleus (VMN)
neurones using the whole-cell voltage-clamp technique with 10 mn;I Ba
2+ as the charge carrier. 2. The steady-state inhibition of the peak h
igh-threshold Ca2+ channel current evoked by depolarization from -80 t
o -10 mV by MA increased in a concentration-dependent fashion. MA inhi
bited a fraction of the whole-cell Ca2+ channel current while progeste
rone had no effect on the peak Ca2+ channel current (7 % at 10 mu M).
The low-threshold Ca2+ (T-type) current, evoked from -100 to -30 mV, w
as unaffected by NIB. 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 sit
e can only be accessed extracellularly. 4. The high-threshold Ca2+ cha
nnel current in VMN neurones was found to consist of four pharmacologi
cally 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 curr
ent. 5. In neurones isolated from cholera toxin-treated animals, the M
A-induced inhibition of the Ca2+ channel current tvas significantly di
minished, suggesting a G-protein alpha(s)-subunit involvement. 6. Trea
tment 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 enhanc
ement induced by MA in cachectic patients may in part be due to a nove
l central nervous system action, that is, inhibition of a fraction of
the whole-cell Ca2+ channel current to attenuate the firing of VMN neu
rones that may be involved in satiety mechanisms.