High-threshold Ca2+ currents in rat hippocampal interneurones and their selective inhibition by activation of GABA(B) receptors.
1. Whole-cell calcium currents were recorded from visually identified inhibitory interneurones located in stratum radiatum (near the border with stratum lacunosum-moleculare) of area. CA1 in rat hippocampal slices. Current-voltage (I-V) relationships in relatively well-clamped neurones showed that inward current activated between -50 and -40 mV (holding potential, -80 mV) and was maximal near -10 mV. Currents showed little inactivation over the course of 85 ms steps, and were completely blocked by removal of Ca2+ or addition of Cd2+. Prominent low-threshold currents were not observed under these conditions. 2. The calcium channels contributing to whole-cell currents in interneurones were examined using selective channel antagonists. The selective N-type calcium channel blocker omega-conotoxin GVIA (omega-CgTX-GVIA; 10 microM) irreversibly blocked 23.2 +/- 2.8% of whole-cell currents. The P/Q-type antagonist omega-agatoxin IVA (omega-Aga-IVA; 1-5 microM) blocked 10.4 +/- 3.3% of whole-cell currents. Block by omega-Aga-IVA was highly variable, ranging from 0 to 30%. The less selective conotoxin, omega-conotoxin MVIIC (omega-CTX-MVIIC; 5 microM) blocked 31.0 +/- 2.7% of whole-cell currents. The selective L-type channel antagonist nifedipine (20 microM) blocked 27.5 +/- 3.5% of whole-cell currents. 3. Whole-cell calcium currents were reversibly inhibited by the selective GABA(B) receptor agonists (+/-)-baclofen or CGP 27492 (1-3 microM; 18.9 +/- 1.4%). This inhibition was reversed or prevented by the selective GABAB receptor antagonist CGP 55845A (1 microM). Inhibition of inward current activated by voltage ramps was voltage dependent, being greatest near -10 mV, and less pronounced at more positive or negative potentials. Inhibition of calcium currents by GABAB receptor agonists was accompanied by an apparent change in the kinetics of whole-cell currents consistent with a slowing of the rate of activation. CGP 27492 depressed calcium currents by 16.1 +/- 1.9% before application of omega-CgTX-GVIA, and by 3.9 +/- 2.0% after application of omega-CgTX-GVIA in the same cells (P < 0.005), consistent with preferential block of N-type calcium channels. 4. Neither adenosine (200 microM) nor the selective mu-opioid receptor agonist Tyr-D-Ala-Gly-MePhe-Gly-ol (DAMGO; 2 microM) inhibited calcium currents. Similarly, CGP 27492, but not adenosine or DAMGO, induced an outward current (at - 70 mV) consistent with activation of inwardly rectifying potassium channels. 5. These results indicate that hippocampal inhibitory neurones located in stratum radiatum possess multiple calcium channel subtypes, including N-type, L-type, and at least two other types of high-threshold channels. Activation of GABAB receptors (but not adenosine or mu-opioid receptors) preferentially inhibits N-type channels in these neurones. Similar inhibition occurring in the terminals of interneurones could contribute to depression of inhibitory synaptic transmission by activation of GABAB autoreceptors.
Lambert
N A
NA
Department of Pharmacology, Duke University Medical Center, Durham NC 27705, USA.
Wilson
W A
WA
D000200:Action Potentials; D000241:Adenosine / Q000494:pharmacology; D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000187:drug effects* / Q000502:physiology*; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D004745:Enkephalins / Q000494:pharmacology; D018755:GABA Agonists / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects* / Q000502:physiology*; D066298:In Vitro Techniques; D007395:Interneurons / Q000502:physiology*; D008297:Male; D009943:Organophosphorus Compounds / Q000494:pharmacology; D010721:Phosphinic Acids / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects; D011412:Propanolamines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018079:Receptors, GABA / Q000187:drug effects*
D000700:Analgesics; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D004745:Enkephalins; D018755:GABA Agonists; D018756:GABA Antagonists; D009943:Organophosphorus Compounds; D010721:Phosphinic Acids; D015221:Potassium Channels; D011412:Propanolamines; D018079:Receptors, GABA; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; C061388:3-aminopropylphosphinic acid; C085075:CGP 55845A; D000241:Adenosine