Human locus coeruleus neurons express the GABA(A) receptor gamma2 subunit gene and produce benzodiazepine binding.
Noradrenergic neurons of the locus coeruleus project throughout the cerebral cortex and multiple subcortical structures. Alterations in the locus coeruleus firing are associated with vigilance states and with fear and anxiety disorders. Brain ionotropic type A receptors for gamma-aminobutyric acid (GABA) serve as targets for anxiolytic and sedative drugs, and play an essential regulatory role in the locus coeruleus. GABA(A) receptors are composed of a variable array of subunits forming heteropentameric chloride channels with different pharmacological properties. The gamma2 subunit is essential for the formation of the binding site for benzodiazepines, allosteric modulators of GABA(A) receptors that are clinically often used as sedatives/hypnotics and anxiolytics. There are contradictory reports in regard to the gamma2 subunit's expression and participation in the functional GABA(A) receptors in the mammalian locus coeruleus. We report here that the gamma2 subunit is transcribed and participates in the assembly of functional GABA(A) receptors in the tyrosine hydroxylase-positive neuromelanin-containing neurons within postmortem human locus coeruleus as demonstrated by in situ hybridization with specific gamma2 subunit oligonucleotides and autoradiographic assay for flumazenil-sensitive [(3)H]Ro 15-4513 binding to benzodiazepine sites. These sites were also sensitive to the alpha1 subunit-preferring agonist zolpidem. Our data suggest a species difference in the expression profiles of the alpha1 and gamma2 subunits in the locus coeruleus, with the sedation-related benzodiazepine sites being more important in man than rodents. This may explain the repeated failures in the transition of novel drugs with a promising neuropharmacological profile in rodents to human clinical usage, due to intolerable sedative effects.
Hellsten
Kati S
KS
Institute of Biomedicine, Pharmacology, Biomedicum Helsinki, POB 63 (Haartmaninkatu 8), FI-00014 University of Helsinki, Finland.
Sinkkonen
Saku T
ST
Hyde
Thomas M
TM
Kleinman
Joel E
JE
Särkioja
Terttu
T
Maksimow
Anu
A
Uusi-Oukari
Mikko
M
Korpi
Esa R
ER
D000328:Adult; D001345:Autoradiography; D001386:Azides / Q000378:metabolism; D001569:Benzodiazepines / Q000378:metabolism*; D005260:Female; D005442:Flumazenil / Q000494:pharmacology; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D006801:Humans; D008125:Locus Coeruleus / Q000378:metabolism*; D008297:Male; D008543:Melanins / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D011869:Radioligand Assay; D011963:Receptors, GABA-A / Q000096:biosynthesis*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D000077334:Zolpidem
D001386:Azides; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; C546240:GABRA1 protein, human; C546279:GABRG2 protein, human; D008543:Melanins; D011725:Pyridines; D011963:Receptors, GABA-A; C014121:neuromelanin; D001569:Benzodiazepines; D005442:Flumazenil; D000077334:Zolpidem; C042957:Ro 15-4513; D014446:Tyrosine 3-Monooxygenase