RAT GROUP-I METABOTROPIC GLUTAMATE RECEPTORS INHIBIT NEURONAL CA2-TRANSDUCTION PATHWAYS IN HEK-293 CELLS( CHANNELS VIA MULTIPLE SIGNAL)

Citation
Ba. Mccool et al., RAT GROUP-I METABOTROPIC GLUTAMATE RECEPTORS INHIBIT NEURONAL CA2-TRANSDUCTION PATHWAYS IN HEK-293 CELLS( CHANNELS VIA MULTIPLE SIGNAL), Journal of neurophysiology, 79(1), 1998, pp. 379-391
Citations number
46
Categorie Soggetti
Neurosciences,Physiology
Journal title
ISSN journal
00223077
Volume
79
Issue
1
Year of publication
1998
Pages
379 - 391
Database
ISI
SICI code
0022-3077(1998)79:1<379:RGMGRI>2.0.ZU;2-2
Abstract
Rat group I metabotropic glutamate receptors inhibit neuronal Ca2+ cha nnels via multiple signal transduction pathways in HEK 293 cells. J. N europhysiol. 79: 379-391, 1998. We have shown previously that metabotr opic glutamate receptors with group I-like pharmacology couple to N-ty pe and P/Q-type calcium channels in acutely isolated cortical neurons using G proteins most likely belonging to the G(i)/G(o) subclass. To b etter understand the potential mechanisms forming the basis for group I mGluR modulation of voltage-gated calcium channels in the CNS, we ha ve examined the ability of specific mGluRs to couple to neuronal N-typ e (alpha(1B-1)/alpha(2) delta/beta(1b)) and P/Q-type (alpha 1(A-2)/alp ha(2) delta/beta(1b)) voltage-gated calcium channels in an HEK 293 het erologous expression system. Using the whole cell patch-clamp techniqu e where intracellular calcium is buffered to low levels, we have shown that group I receptors inhibit both N-type and P/Q-type calcium chann els in a voltage-dependent fashion. Similar to our observations in cor tical neurons, this voltage-dependent inhibition is mediated almost en tirely by N-ethylmaleimide (NEM)-sensitive heterotrimeric G proteins, strongly suggesting that these receptors can use G(i)/G(o)-like G prot eins to couple to N-type and P/Q-type calcium channels. However, incon sistent with the apparent NEM sensitivity of group I modulation of cal cium channels, modulation of N-type channels in group I mGluR-expressi ng cells was only partially sensitive to pertussis toxin (PTX), indica ting the potential involvement of both PTX-sensitive and -resistant G proteins. The PTX-resistant modulation was voltage dependent and entir ely resistant to NEM and cholera toxin. A time course of treatment wit h PTX revealed that this toxin caused group I receptors to slowly shif t from using a primarily NEM-sensitive G protein to using a NEM-resist ant form. The PTX-induced switch from NEM-sensitive to -resistant modu lation was also dependent on protein synthesis, indicating some relian ce on active cellular processes. In addition to these voltage-dependen t pathways, perforated patch recordings on group I mGluR-expressing ce lls indicate that another slowly developing, calcium-dependent form of modulation for N-type channels may be seen when intracellular calcium is not highly buffered. We conclude that group I mGluRs can modulate neuronal Ca2+ channels using a variety of signal transduction pathways and propose that the relative contributions of different pathways may exemplify the diversity of responses mediated by these receptors in t he CNS.