Modulation by different GABAB receptor types of voltage-activated calcium currents in rat thalamocortical neurones.
1. The effects of the GABAB receptor agonist baclofen on the voltage-dependent Ca2+ currents were studied in rat thalamocortical neurones with the use of whole cell voltage-clamp recordings in brain slices. 2. The contribution of N-, L- and P-types of Ca2+ channels to the total high voltage-activated Ca2+ (HVA Ca2+) current was assessed by the use of omega-conotoxin, nifedipine and omega-agatoxin IVA, respectively. No P-type current could be detected. Thus, the HVA Ca2+ current contained an N- and an L-type current (23 and 15% of the total current, respectively) and a residual current, which will be referred to as the 'R' component. 3. Baclofen (1-50 microM) had no effect on the low voltage-activated (LVA) Ca2+ current (IT). 4. At low concentrations (0.5-10 microM), baclofen decreased the HVA Ca2+ currents by about 10-20% without a marked modification on the kinetics, whereas 50 microM baclofen decreased the HVA Ca2+ currents by about 40% with a pronounced slowing down of the kinetics. 5. The 10-20% decrease of the total HVA Ca2+ currents produced by the low concentrations of baclofen occurred as the result of a 30% block of the 'R' component. The additional decrease observed with the dose of 50 microM was due to a full block of the N-type current. The L-type was unaffected by baclofen. 6. The effect of baclofen on the total HVA Ca2+ current was partially blocked by GABAB receptor antagonists indicating that it occurred through stimulation of GABAB receptors. 7. The effect of baclofen on the N-type current was abolished by CGP 35348 (100 microM) and CGP 55845A (100 nM). The effect on the 'R' component was also antagonized by CGP 55845A (100 nM) although with a lower potency, but was not blocked by CGP 35348 (100 microM). 8. We conclude that the effects of baclofen on the various components of the HVA Ca2+ currents occur through different types of GABAB receptors. One receptor has a high affinity for baclofen (i.e. saturated by concentrations as low as 0.5 microM), is insensitive to CGP 35348, is coupled to the 'R' component and is responsible for a maximum 20% decrease in the total HVA Ca2+ current. The other receptor has a lower affinity for baclofen (i.e. affected by a concentration of 50 microM), is sensitive to CGP 35348, is coupled to the N-type Ca2+ current and is responsible for the additional 20-30% decrease in the HVA Ca2+ current observed with 50 microM baclofen.
Guyon
A
A
Laboratoire de Neurobiologie Cellulaire, Institut des Neurosciences, URA 1488 CNRS, Université Pierre et Marie Curie, Paris, France.
Leresche
N
N
D000818:Animals; D001418:Baclofen / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000378:metabolism*; D002540:Cerebral Cortex / Q000166:cytology / Q000378:metabolism*; D004594:Electrophysiology; D058788:GABA-B Receptor Antagonists; D005829:Geniculate Bodies / Q000187:drug effects; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D010455:Peptides / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D018080:Receptors, GABA-B / Q000378:metabolism*; D013788:Thalamus / Q000166:cytology / Q000378:metabolism*; D020866:omega-Conotoxin GVIA
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D058788:GABA-B Receptor Antagonists; D010455:Peptides; D018080:Receptors, GABA-B; D020866:omega-Conotoxin GVIA; D001418:Baclofen