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Vol. 58, Issue 2, 373-379, August 2000
2-Adrenoceptor Antibody Behave as
Antagonists
Laboratorio de Permeabilidad Iónica, Centro de
Biofísica y Bioquímica, Instituto Venezolano de
Investigaciones Científicas, Caracas, Venezuela (A.M.);
Département de Biochimie et Groupe de recherche sur le
Système Nerveux Autonome, Université de Montréal,
Canada (D.L.); Max Delbrück Center for Molecular Medicine,
Berlin, Germany (G.W.); and UPR9021 du Centre National de la Recherche
Scientifique, Institute for Molecular and Cellular Biology, Strasbourg,
France (J.H.)
We previously demonstrated that the monoclonal antibody Mab6H8 raised
against the second extracellular loop of the
2-adrenoceptor (2-AR) had an agonist-like
activity, mediated by the activation of L-type Ca2+
channels by protein kinase A through the adenylyl cyclase
pathway. We suggested that this Mab acts by stabilizing an active
dimeric conformation of the 2-AR. To substantiate this
hypothesis, we prepared monomeric Fab fragments of Mab6H8. Comparison
of the physicochemical parameters of antigen interaction with both the Mab and its Fab fragments were determined by surface plasmon resonance, showing a 5- to 10-fold lower affinity of the fragments compared with
the bivalent antibody. We determined the biological activity of
antibody and Fab fragments in two systems: spontaneous beating neonatal
rat cardiomyocytes to study the chronotropic effects and isolated
guinea pig cardiomyocytes to study L-type Ca2+ channel
activation. Fab fragments as such had no "agonist-like" effects in
both systems but inhibited receptor activation with the
2-specific agonist clenbuterol. Addition of a
cross-linking rabbit anti-mouse IgG restored the agonist-like effect of
the Fab fragments. These results suggest that Fab fragments induce a
conformational change in the receptor, inhibiting the accessibility of
the pharmacophore pocket to clenbuterol. Dimerization of this receptor
conformation induces an agonist-like effect. Antireceptor antibodies
can thus act both as agonist in the dimeric state and as antagonist in
the monomeric state.
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