Alpha 1-adrenoceptors in rat dorsal raphe neurons: regulation of two potassium conductances.
1. alpha 1-Adrenoceptor activation caused two separate effects in rat dorsal raphe neurons: a depolarization and an increase in the duration of the after-hyperpolarization following the action potential. The depolarization often resulted in repetitive action potentials. The alpha 1-adrenoceptor antagonists prazosin and WB 4101 blocked the depolarization induced by phenylephrine. The concentration-response curve to phenylephrine was shifted to the right by WB 4101. 2. Under voltage clamp, alpha 1-adrenoceptor agonists caused an inward current at -60 mV, which often became smaller at negative potentials but rarely reversed polarity even at strongly negative potentials. Using whole-cell recording, the inward current reversed polarity at the equilibrium potential for potassium in the majority of cells. Intracellular Cs+ decreased or abolished the alpha 1-mediated inward current. The inward current was dependent on external calcium, but not on the degree of internal calcium buffering. Removal of external calcium or addition of MgCl2, CoCl2 or CdCl2 reduced or blocked the effects of alpha 1-adrenoceptor agonists. Barium and strontium supported and even augmented the inward current induced by alpha 1-adrenoceptor agonists, whereas nifedipine and omega-conous toxin had no effect. In contrast, internal dialysis with the calcium chelator 1,2-bis(O-aminophenoxy)ethane-N,N,N'N'-tetraacetic acid (BAPTA) did not inhibit the inward current. 3. The alpha 1-induced depolarization was blocked (or occluded) by the inclusion of GTP-gamma-S (100 microM) in the recording pipette. The phorbol-ester 4-phorbol 12,13-dibutyrate (PDBu) had no action on the membrane potential and depressed the phenylephrine-induced depolarization. This depression was reversed by the non-selective protein kinase inhibitor staurosporin. 4. Phenylephrine and noradrenaline increased a late component of the after-hyperpolarization (late-AHP) that followed a single action potential. The alpha 1-sensitive late-AHP was blocked by apamine suggesting that it is a calcium-dependent potassium conductance. 5. Thapsigargin reduced the duration of the late-AHP and blocked the phenylephrine-mediated prolongation. Caffeine also augmented the late-AHP and ryanodine blocked the augmentation induced by caffeine. The augmentation induced by phenylephrine was not occluded by caffeine and was still present after the caffeine-induced augmentation was blocked by ryanodine. 6. In slices pretreated with manoalide the depolarization induced by alpha 1-agonists was not changed; however, the late-AHP was reduced in duration and the alpha 1-receptor-mediated augmentation of the late-AHP was decreased.(ABSTRACT TRUNCATED AT 400 WORDS)
Pan
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Vollum Institute, Oregon Health Sciences University, Portland 97201.
Grudt
T J
TJ
Williams
J T
JT
D058646:Adrenergic alpha-1 Receptor Agonists; D058668:Adrenergic alpha-1 Receptor Antagonists; D000818:Animals; D001030:Apamin / Q000494:pharmacology; D001711:Biotransformation / Q000187:drug effects; D002104:Cadmium / Q000494:pharmacology; D002110:Caffeine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism / Q000502:physiology; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000502:physiology; D006636:Histamine Release / Q000187:drug effects; D066298:In Vitro Techniques; D009467:Neuromuscular Depolarizing Agents / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D009638:Norepinephrine / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology; D010703:Phorbol Esters / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology*; D011903:Raphe Nuclei / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D018340:Receptors, Adrenergic, alpha-1 / Q000502:physiology*; D013729:Terpenes / Q000494:pharmacology; D019284:Thapsigargin; D010738:Type C Phospholipases / Q000378:metabolism
D058646:Adrenergic alpha-1 Receptor Agonists; D058668:Adrenergic alpha-1 Receptor Antagonists; D009467:Neuromuscular Depolarizing Agents; D010703:Phorbol Esters; D015221:Potassium Channels; D018340:Receptors, Adrenergic, alpha-1; D013729:Terpenes; D002104:Cadmium; D010656:Phenylephrine; D001030:Apamin; D002110:Caffeine; D019284:Thapsigargin; D010738:Type C Phospholipases; D019204:GTP-Binding Proteins; D002118:Calcium; D009638:Norepinephrine