Dihydropyridine- and omega-conotoxin-sensitive Ca2+ currents in cerebellar neurons: persistent block of L-type channels by a pertussis toxin-sensitive G-protein.
The inhibition of high-threshold Ca2+ channel currents by activated G-proteins was studied in mouse cerebellar granule cells making use of the hydrolysis-resistant GTP analog GTP-gamma-S. When individual granule cells were internally dialyzed with GTP-gamma-S, the high-threshold Ca2+ current decreased to approximately 20% of its initial value within approximately 2 min. The GTP-gamma-S-resistant current was reduced further by the subsequent addition of either omega-conotoxin or dihydropyridine antagonist, indicating that both N- and L-type Ca2+ channels carried the remaining current. Continuous exposure to the dihydropyridine agonist +(S)-202-791 caused a rapid increase in the GTP-gamma-S-resistant current. The L-type current evoked by the agonist subsequently decreased to the level observed prior to adding the drug following a time course similar to the initial inhibition of the total high-threshold current. A second application of the drug at a later time failed to increase the current a second time, indicating a persistent blockade of the agonist-evoked L-current. Pretreating cells with pertussis toxin prevented the initial inhibition of the total whole-cell Ca2+ channel current as well as the subsequent inhibition of the agonist-evoked L-current. The results show that a pertussis toxin-sensitive G-protein produces a persistent inhibition of L-type Ca2+ channels in these central neurons.
Department of Pharmacology, School of Medicine, University of California, San Francisco 94143-0450.
C M
CM
Haws
P A
PA
Slesinger
J B
JB
Lansman
D000818:Animals; D002104:Cadmium / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015220:Calcium Channels / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D002531:Cerebellum / Q000502:physiology*; D004095:Dihydropyridines / Q000494:pharmacology*; D004553:Electric Conductivity / Q000187:drug effects; D005071:Evoked Potentials / Q000187:drug effects; D019204:GTP-Binding Proteins / Q000502:physiology*; D005682:Gadolinium / Q000494:pharmacology; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000494:pharmacology; D007700:Kinetics; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D010456:Peptides, Cyclic / Q000494:pharmacology*; D037342:Pertussis Toxin; D013997:Time Factors; D010566:Virulence Factors, Bordetella / Q000494:pharmacology*; D020960:omega-Conotoxins
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D004095:Dihydropyridines; D010456:Peptides, Cyclic; D010566:Virulence Factors, Bordetella; D020960:omega-Conotoxins; D002104:Cadmium; C053423:Conus magus toxin; D016244:Guanosine 5'-O-(3-Thiotriphosphate); C038806:1,4-dihydropyridine; D005682:Gadolinium; D037342:Pertussis Toxin; D019204:GTP-Binding Proteins