RT Journal Article
SR Electronic
T1 Binding, Partial Agonism, and Potentiation of α<sub>1</sub>-Adrenergic Receptor Function by Benzodiazepines: A Potential Site of Allosteric Modulation
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 1164
OP 1171
VO 291
IS 3
A1 David J. J. Waugh
A1 Robert J. Gaivin
A1 Derek S. Damron
A1 Paul A. Murray
A1 Dianne M. Perez
YR 1999
UL http://jpet.aspetjournals.org/content/291/3/1164.abstract
AB Benzodiazepines, a class of drugs commonly used to induce anesthesia and sedation, can attenuate intracellular calcium oscillations evoked by α1-adrenergic receptor (α1-AR) stimulation in pulmonary artery smooth muscle cells. We postulated a direct action of benzodiazepines in modulating α1-AR function at the receptor level. Benzodiazepines bound to each of the cloned α1-AR subtypes (α1a-, α1b-, or α1d-AR) on COS-1 cell membranes transiently transfected to express a single population of α1-AR subtype. The ability of benzodiazepines to alter α1-AR signal transduction was investigated by measuring total inositol phosphate generation in rat-1 fibroblast cells, stably transfected to express a single α1-AR subtype. By themselves, benzodiazepines displayed partial agonism. At α1b-ARs and α1d-ARs, the maximal inositol phosphate response to phenylephrine was potentiated almost 2-fold by either midazolam or lorazepam (100 μM). At α1a-ARs, diazepam, lorazepam, and midazolam all increased the maximal response of the partial agonist clonidine at these receptors, whereas the response to the full agonist phenylephrine was unaltered or inhibited. The potentiating actions of midazolam and its partial agonism at α1-ARs was blocked by the addition of 1 μM prazosin, an α1-AR antagonist, and not by a γ-aminobutyric acidA-receptor antagonist. These studies show that benzodiazepines modulate the function of α1-ARs in vitro, and this is the first report of a potential allosteric site on α1-ARs that may be therapeutically useful for drug design. The American Society for Pharmacology and Experimental Therapeutics