title: Alpha1A-adrenergic receptors are functionally expressed by a subpopulation of cornu ammonis 1 interneurons in rat hippocampus.
abstract: The importance of adrenergic receptors (ARs) in the hippocampus has generally focused on betaARs; however, interest is growing in hippocampal alphaARs given their purported neuroprotective role. We have previously reported alpha(1)AR transcripts in a subpopulation of cornu ammonis 1 (CA1) interneurons. The goal of this study was to identify the specific alpha(1)AR subtype (alpha(1A), alpha(1B), alpha(1D)) functionally expressed by these cells. Using cell-attached recordings to measure action potential frequency changes, concentration-response curves for the selective alpha(1)AR agonist phenylephrine (PE) were generated in the presence of competitive subtype-selective alpha(1)AR antagonists. Schild regression analysis was then used to estimate equilibrium dissociation constants (K(b)) for each receptor antagonist in our system. The selective alpha(1A)AR antagonists, 5-methylurapidil and WB-4101 [2-[(2,6-dimethoxyphenoxyethyl)aminomethyl]-1,4-benzodioxane hydrochloride], produced consecutive rightward shifts in the concentration-response curve for PE when used at discriminating, nanomolar concentrations. Calculated K(b) values for 5-methylurapidil (10 nM) and WB-4101 (5 nM) correlate to previously published affinity values for these antagonists at the alpha(1A)AR. The selective alpha(1B)AR antagonist L-765,314 [(2S)-4-(4-amino-6,7-dimethoxy-2-quinazolinyl)-2-[[(1,1-dimethylethyl)amino]carbonyl]-1-piperazinecarboxylic acid], as well as the selective alpha(1D)AR antagonist BMY7378 [8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro[4.5]decane-7,9-dione dihydrochloride], produced significant rightward shifts in the concentration-response curve for PE only when used at nondistinguishing, micromolar concentrations. Calculated K(b) values for L-765,314 (794 nM) and BMY7378 (316 nM) do not agree with affinity values for these antagonists at the alpha(1B) or alpha(1D)AR, respectively. Rather, these K(b) values more closely match equilibrium dissociation constants estimated for these compounds when used to identify alpha(1A)AR subtypes. Together, our results provide strong evidence to support functional expression of alpha(1A)ARs in a subpopulation of CA1 interneurons.
authors.affiliation: Department of Pharmacology, Physiology, and Therapeutics, University of North Dakota School of Medicine and Health Sciences, 501 North Columbia Road, Stop 9037, Grand Forks, North Dakota 58202-9037, USA.
authors.forename: Kristin L
authors.initials: KL
authors.lastname: Hillman
authors.forename: Van A
authors.initials: VA
authors.lastname: Doze
authors.forename: James E
authors.initials: JE
authors.lastname: Porter
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D058646:Adrenergic alpha-1 Receptor Agonists; D058668:Adrenergic alpha-1 Receptor Antagonists; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D003000:Clonidine / Q000494:pharmacology; D004146:Dioxanes / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology*; D066298:In Vitro Techniques; D007395:Interneurons / Q000187:drug effects / Q000502:physiology*; D007545:Isoproterenol / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011224:Prazosin / Q000031:analogs & derivatives / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018340:Receptors, Adrenergic, alpha-1 / Q000502:physiology*
chemical_list: C547715:Adra1a protein, rat; C547718:Adra1b protein, rat; C547721:Adra1d protein, rat; D058646:Adrenergic alpha-1 Receptor Agonists; D058668:Adrenergic alpha-1 Receptor Antagonists; D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D004146:Dioxanes; C111640:L 765314; D010879:Piperazines; D018340:Receptors, Adrenergic, alpha-1; C057446:5-methylurapidil; D010656:Phenylephrine; C010654:(2-(2',6'-dimethoxy)phenoxyethylamino)methylbenzo-1,4-dioxane; C053428:BMY 7378; D007545:Isoproterenol; D003000:Clonidine; D011224:Prazosin