Analysis of the Pharmacological and Molecular Heterogeneity of I₂-Imidazoline-Binding Proteins using Monoamine Oxidase-Deficient Mouse Models

Abstract

The I 2 subgroup of imidazoline-binding sites was identified as monoamine oxidases (MAOs), but it is unclear whether there are I 2 -binding sites located on proteins distinct from MAOs. photolabeled three proteins with apparent molecular masses of ϳ28 (liver), ϳ61 (brain), and ϳ55 kDa (liver and brain). The photolabeling of each protein was blocked by the imidazoline cirazoline (10 M). Photolabeling of the ϳ61-and ϳ55-kDa proteins was not observed in MAO A and B KO mice, respectively. In contrast, photolabeling of the liver ϳ28-kDa protein was still observed in MAO-deficient mice, indicating that this protein is unrelated to MAOs. These data indicate that I 2 imidazoline-binding sites identified by [ 3 H]idazoxan reside solely on MAO B. The binding sites on MAO A and the liver ϳ28-kDa protein may represent additional subtypes of the family of the imidazoline-binding sites.

Angiotensin I-Converting Enzyme Inhibition Increases Cardiac Catecholamine Content and Reduces Monoamine Oxidase Activity via an Angiotensin Type 1 Receptor-Mediated Mechanism

“…Whereas enalapril has no in vitro effect, captopril increases MAO activity, which may indicate an allosteric binding site. The imidazoline I 2 binding site has been characterized as exactly such an allosteric site in this context (Tesson et al, 1995;Raasch et al, 1999b;Remaury et al, 2000). However, the binding of guanidine or imidazoline derivatives to this site inhibited, rather than stimulated, MAO activity (Raasch et al, 1999b), and the structure of captopril is so unrelated to these ligands that an important interaction appears unlikely.…”

Locomotor effects of imidazoline I2‐site‐specific ligands and monoamine oxidase inhibitors in rats with a unilateral 6‐hydroxydopamine lesion of the nigrostriatal pathway

“…The functional significance of the sites in the basal ganglia is unknown, since neither their molecular structure nor their second-messenger systems have been elucidated. However, there is extensive evidence that imidazoline I 2 -binding sites exist on monoamine oxidase (MAO), at a location distinct from the catalytic site (Alemany et al, 1995;Raddatz et al, 1997;Remaury et al, 2000). In vitro, many imidazolines, including 2-BFI and BU224, reversibly inhibit MAO-A with a similar potency to that of the reversible MAO-A inhibitor moclobemide (IC 50 : 2-BFI, 16.572.7 mM; BU224, 4.870.2 mM; moclobemide, 3673.6 mM; Lalies et al, 1999).…”

Potentiation of Ligand Binding through Cooperative Effects in Monoamine Oxidase B

“…A number of studies have identified the outer membrane mitochondrial enzymes, monoamine oxidases A and B (MAO A 5 and MAO B), as possessing I 2 -binding sites. These studies range from photoaffinity labeling (2,3) to I 2 -binding site population analysis in MAO (A or B)-deficient transgenic mice (4,5). However, a great deal of uncertainty exists in the literature in understanding the molecular nature of these interactions.…”