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Residual Ca2+ channel current modulation by megestrol acetate via a G‐protein alpha s‐subunit in rat hypothalamic neurones.
Author(s) -
Costa A M,
Spence K T,
Plata-Salamán C R,
ffrenchMullen J M
Publication year - 1995
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1113/jphysiol.1995.sp020880
Subject(s) - chemistry , endocrinology , biophysics , depolarization , medicine , extracellular , patch clamp , intracellular , biology , electrophysiology , biochemistry
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.