Orexins cause depolarization via nonselective cationic and K+ channels in isolated locus coeruleus neurons.
The locus coeruleus (LC) contains noradrenergic neurons that are innervated by orexin (ORX)-like immunoreactive axons and express both orexin receptor-1 and -2. We studied effects of ORX-A and -B (ORX-A/B) on dissociated LC neurons by using whole-cell patch clamp techniques. In current-clamp mode, LC neurons were depolarized by application of ORX-A (10(-7) M) [53% of neurons tested; 9.0+/-0.2 mV (n=5)], or ORX-B (10(-7) M) [38% of neurons tested; 4.0+/-0.1 mV (n=5)]. Firing frequencies of action potentials increased during application [1.1+/-0.2 Hz (n=5) in ORX-A; 0.8+/-0.2 Hz (n=5) in ORX-B] and returned to the control level [0.2+/-0.1 Hz (n=5)] after removal. The ORX-A/B-induced depolarization was well maintained in the presence of TTX (3x10(-7) M), CNQX (10(-6) M) and AP5 (10(-5) M). In voltage-clamp mode, removal of external Na+ suppressed both ORX-A/B-induced currents and shifted their reversal potentials from approximately -45 mV to -60 mV. In addition, ORX-A/B inhibited sustained K+ currents. These results suggest that ORX-A/B increase the firing frequency of LC neurons through the depolarization probably produced by both augmentation of the nonselective cationic conductance and inhibition of the sustained K+ conductance.
Murai
Yoshinaka
Y
Department of Oral Functional Science (Physiology), Graduate School of Dental Medicine, Hokkaido University, Kita 13 Nishi 7, Kita-ku, Sapporo 060-8586, Japan. murai@den.hokudai.ac.jp
Akaike
Tadashi
T
D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D015761:4-Aminopyridine / Q000494:pharmacology; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004558:Electric Stimulation / Q000379:methods; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins / Q000145:classification / Q000494:pharmacology*; D007473:Ion Channels / Q000187:drug effects / Q000378:metabolism; D008125:Locus Coeruleus / Q000166:cytology*; D008564:Membrane Potentials / Q000187:drug effects; D009474:Neurons / Q000187:drug effects* / Q000528:radiation effects; D009479:Neuropeptides / Q000145:classification / Q000494:pharmacology*; D000068797:Orexins; D018408:Patch-Clamp Techniques / Q000379:methods; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D026941:Sodium Channel Blockers / Q000494:pharmacology; D019789:Tetraethylammonium / Q000494:pharmacology; D013779:Tetrodotoxin / Q000494:pharmacology
D018691:Excitatory Amino Acid Antagonists; D047908:Intracellular Signaling Peptides and Proteins; D007473:Ion Channels; D009479:Neuropeptides; D000068797:Orexins; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D026941:Sodium Channel Blockers; D013779:Tetrodotoxin; D019789:Tetraethylammonium; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D015763:2-Amino-5-phosphonovalerate; D015761:4-Aminopyridine