title: Agonistic antibody to the alpha1-adrenergic receptor mobilizes intracellular calcium and induces phosphorylation of a cardiac 15-kDa protein.
abstract: Hypertension is a major cause for hypertrophic remodelling of the myocardium. Agonistic autoantibodies to extracellular loops of the alpha(1)-adrenergic receptor (alpha(1)-AR) have been identified in patients with arterial hypertension. However, intracellular reactions elicited by these agonistic antibodies remain elusive. An anti-peptide antibody (anti-alpha(1)) was generated against the second extracellular loop of the alpha(1)-AR that bound to its peptide epitope with high affinity (K (D) approximately 50 nM). We studied anti-alpha(1) effects on intracellular calcium (Ca(i)), a key factor in cellular remodelling, and receptor-mediated cardiac protein phosphorylation. Anti-alpha(1) induced pronounced but transient increases in Ca(i) in CHO cells expressing the human alpha(1)-AR (CHO-alpha(1)) and in neonatal cardiomyocytes. Preincubation experiments failed to demonstrate a tonic effect of anti-alpha(1) on Ca(i). However, preincubation with the antibody attenuated the effect of the alpha(1)-AR antagonist prazosin. In neonatal cardiomyocytes anti-alpha(1) induced a robust phosphorylation of a 15-kDa protein that is involved in alpha(1)-AR signalling. Our data support the notion that elevation of Ca(i) is a general feature of agonistic antibodies' action and constitute an important pathogenic component of hypertension-associated autoantibodies. Furthermore, we suggest that agonistic antibodies to the alpha(1)-AR contribute to hypertrophic remodelling of cardiac myocytes, and that the cardiac 15-kDa protein is a relevant downstream target of their action.
authors.affiliation: ERDE eV, Campus Berlin-Buch, Building 55 (OCVH), Robert-Rössle-Strasse 10, 13125, Berlin, Germany. karczewski@aak-diagnostik.de
authors.forename: Peter
authors.initials: P
authors.lastname: Karczewski
authors.forename: Hannelore
authors.initials: H
authors.lastname: Haase
authors.forename: Petra
authors.initials: P
authors.lastname: Hempel
authors.forename: Marion
authors.initials: M
authors.lastname: Bimmler
mesh_terms: D058646:Adrenergic alpha-1 Receptor Agonists; D000818:Animals; D000831:Animals, Newborn; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D001323:Autoantibodies; D016466:CHO Cells; D020013:Calcium Signaling; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D032383:Myocytes, Cardiac / Q000737:chemistry*; D010766:Phosphorylation; D011506:Proteins / Q000378:metabolism*; D051381:Rats; D018340:Receptors, Adrenergic, alpha-1 / Q000235:genetics / Q000502:physiology*; D014162:Transfection
chemical_list: D058646:Adrenergic alpha-1 Receptor Agonists; D000911:Antibodies, Monoclonal; D001323:Autoantibodies; D011506:Proteins; D018340:Receptors, Adrenergic, alpha-1
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